Nanomaterial-based strategies to modulate macrophage polarization in osteoarthritis: A systematic review.

Bee sting acupuncture mitigates osteoarthritis in male mice via PPAR-γ activation: integrated network pharmacology, transcriptomics, and experimental validation.

Cytotoxicity is a major pathological effect that can occur during snakebite envenoming. To better understand the underlying biochemical and molecular mechanisms behind snake venom-induced cytotoxicity, it is essential to use appropriate in vitro tools for bioassaying cytotoxicity evoked by snake venoms. Identifying the toxins causing cytotoxicity is also important in this regard, particularly in the context of developing more effective snakebite treatments. Cytotoxicity induced by venom toxins can result in local pathologies in snakebite victims, which can result in long-term morbidity, and is frequently observed after bites by medically important vipers. In the present study, we optimized and applied an analytical cytotoxicity profiling platform for in vitro cytotoxicity assessment of viper venoms. Using four cell lines (RPTEC/TERT1, HepaRG, iPSC-EC, HaCat), we applied an imaging analysis assay together with resazurin reduction to identify the mechanisms of cytotoxicity at the level of cell necrosis, extracellular matrix (ECM) degradation and/or cell apoptosis. Strong cytotoxic peaks are consistent with ECM-associated cytotoxic effects, as reflected by pronounced reductions in cell area and monolayer integrity. These cytotoxicity bioassays were integrated into nanofractionation analytics and high throughput venomics, which allowed for the identification of viper venom cytotoxins at the biological and chemical levels. Venom profiling showed ECM degradation as the main cytotoxic mechanism, except for Daboia russelii, which induced necrosis and apoptosis in three cell lines. Cytotoxicity largely disappeared after reversed-phase separation, prompting use of non-denaturing SEC in nanofractionation analytics, which revealed strong cytotoxic peaks for Bothrops jararaca and Calloselasma rhodostoma in RPTEC/TERT1 cells. The methodology presented here combined analytical and biochemical tools allowing rapid cytotoxicity profiling of viper venom toxins in parallel with toxin identification.

HYAL2-generated low-molecular-weight hyaluronic acid promotes intervertebral disc degeneration via the CD44/AKT signaling axis.

Engineered bacterial outer membrane vesicles enhanced tumor immunotherapy through remodeling tumor stroma and targeted delivery of CD73 siRNA.

Mast cell characterization, density, and distribution in placenta accreta spectrum: A histological, histochemical and immunohistochemical analysis.

Duhuo Jisheng decoction alleviates knee osteoarthritis via synovial mesenchymal stem cell-derived exosomes mediating the microRNA-194-5p/wnt signaling pathway.

Osteoarthritis (OA) is a degenerative disease with incompletely understood mechanisms. The proteasome subunit PSMB9 has been implicated in immune regulation, but its specific role in OA pathogenesis remains unclear. This study aimed to investigate whether PSMB9 mediates IL-1β-induced chondrocyte injury by activating the NF-κB pathway through promoting IκBα degradation, and to explore the regulatory relationship between IL-6 and PSMB9 in OA progression. Differentially expressed genes were identified by integrating human and mouse OA datasets. A mouse destabilization of the medial meniscus (DMM) model was established. The function of PSMB9 in OA chondrocytes and its effect on the NF-κB pathway were analyzed using hematoxylin-eosin (H&E) staining, immunohistochemistry, Western blot, CCK-8, Edu, flow cytometry, and immunofluorescence to observe p65 nuclear translocation. (1) PSMB9 was significantly upregulated in multiple OA datasets and models; (2) PSMB9 expression increased in the cartilage of OA patients and mice; (3) PSMB9 overexpression exacerbated IL-1β-induced chondrocyte apoptosis, inhibited proliferation, upregulated the expression of the inflammatory factor IL-6 and the matrix-degrading enzyme MMP13, promoted extracellular matrix (ECM) degradation, and decreased COL2A1 expression; (4) PSMB9 activated the NF-κB pathway by promoting IκBα degradation, and inhibition of this pathway alleviated cell injury; (5) silencing IL-6 reduced PSMB9 expression. PSMB9 may participate in the activation of the NF-κB pathway and potentially contribute to chondrocyte injury in OA, making it a promising target for future research.

As a widespread chronic degenerative joint disease that predominantly affects elderly populations worldwide, osteoarthritis (OA) is pathologically defined by the gradual breakdown of extracellular matrix (ECM), cellular apoptosis, and inflammatory processes. Asperuloside (ASP), an iridoid glycoside compound, demonstrates broad bioactivity encompassing inflammation modulation and oxidative stress mitigation across disease models. Nevertheless, the potential of ASP for OA treatment and its associated molecular mechanisms have not yet been completely deciphered. This investigation sought to clarify the therapeutic mechanisms of ASP in OA, thus providing experimental evidence supporting its potential as a novel disease-modifying treatment. Western blotting and immunofluorescent assay were utilized to explore ASP's protective role against IL-1β-mediated damage in primary chondrocytes invitro. Healing effect of ASP was evaluated via micro-CT imaging, histopathological analysis and immunohistochemical staining were conducted using a rat model with destabilized medial meniscus (DMM) invivo. ASP reversed IL-1β-induced pathological effects, including ECM degradation, inflammatory mediator secretion, and cellular apoptosis in chondrocytes. In the DMM rat model, ASP attenuated cartilage degeneration. Mechanistically, it suppressed OA progression via Nrf2/HO-1/NQO1 pathway signaling, suppressing both NF-κB activation and ROS accumulation. ASP alleviated OA progression by inhibiting chondrocyte apoptosis, inflammatory responses, and ECM degradation in both cellular and DMM rat models through Nrf2-mediated suppression of NF-κB signaling. Collectively, ASP may be a promising disease-modifying drug for OA.

Osteoarthritis (OA) is a severe chronic inflammatory disorder with limited treatment options. Naringin (nar) has been shown to protect against OA; however, its mechanisms of action on OA remain poorly understood. This study aims to investigate the molecular mechanism of nar in treating OA via network pharmacology and experiments. Differentially expressed genes (DEGs) were identified using GSE283079 dataset. Protein-protein interaction (PPI) network was constructed using STRING database, and protein interactions were analyzed. Network pharmacology was employed to investigate the molecular interaction network influenced by nar in OA, and molecular docking was applied to predict the binding interactions between nar and core genes. The OA mouse models were constructed using anterior cruciate ligament transection (ACLT) to explore the action of nar in vivo. The OA damage was examined using Hematoxylin and Eosin (HE) and Safranin-O/Fast Green staining, along with Osteoarthritis Research Society International (OARSI) scoring for quantitative histopathological evaluation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive rate and inflammation factor (tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta), and reactive oxygen species (ROS) levels were detected using corresponding assay kits. The protein expression was analyzed using western blot. Cell viability and cell apoptosis were examined using cell counting kit 8 (CCK8) assay kit and flow cytometry assays. In GSE283079 dataset, the up-regulation of DEGs was enriched in immune response activation, cartilage development, collagen metabolic process, and leukocyte proliferation. Additionally, matrix metalloproteinase 13 (MMP13), MMP1, and phospholipase A2 group IIA (PLA2G2A) may be the core genes for nar-protected OA. The binding energy of nar and MMP13 was strongest. In vivo OA models, nar mitigated OA progression and reduced OARSI scores. Mechanistically, nar suppressed cell apoptosis, inflammation factor productions, extracellular matrix (ECM) degradation, and ROS production via decreasing MMP13. Nar alleviates OA malignant progression via reducing MMP13. Key words Osteoarthritis " Naringin " Network pharmacology " MMP13 " Molecular mechanism.

Neutrophil-extracellular traps are net-like material released by triggered neutrophils and composed of decondensed chromatin linked to nuclear proteins. Elastase, one of the fourth most represented neutrophil-specific serine proteases stored in azurophil granules of naïve neutrophils, exerts various actions, including degradation of extracellular matrix and has proinflammatory functions. Plasma was obtained from 111 patients with various hematological malignancies and 42 healthy donors, and plasma elastase levels were measured by ELISA. Reduced circulating levels of neutrophil elastase were found in patients with myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia, while they were increased in acute myeloid leukemia (AML) and non-Hodgkin lymphomas (NHL), with statistically significant AUCs (AML, AUC = 0.7821 and p = 0.0182; and NHL, AUC = 0.7521 and p = 0.0008). Moreover, multiple patients with standard-risk genetic features tended to have higher plasma elastase levels compared to healthy controls. Patients were then divided into two groups, using a cut-off of 300 ng/mL of plasma elastase, and clinical outcomes were compared, showing reduced overall survival and progression-free survival in those subjects with increased plasma elastase levels, as well as shorter time-to-treatment. Our findings indicate that circulating plasma elastase could be useful to distinguish across diseases in the differential diagnosis of hematological malignancies, and could be used as additional prognostic biomarker of disease progression and responsiveness to therapies.

Brain metastasis (BrM) is a leading cause of mortality in patients with lung adenocarcinoma (LUAD). Extracellular vesicles (EVs), which carry bioactive molecules, play a critical role in tumor microenvironment remodeling and exhibit metastatic organotropism, holding promise as liquid biopsy biomarkers. This study aims to identify plasma EV-derived proteins associated with LUAD-BrM. A multi-omics framework was applied. Plasma EVs from 59 stage IV LUAD patients (30 BrM vs 29 non-BrM) were profiled using data-independent acquisition mass spectrometry proteomics. Candidate proteins were screened via bioinformatics and machine learning (LASSO/RF/SVM). Initial validation included tissue proteomics (n = 13), single-cell transcriptomics (TISCH2), and Western blot analysis of a subset of the discovery samples. Functional experiments were conducted in vitro. The lead candidate was ultimately validated in an independent plasma cohort (n = 158) through ELISA. Proteomic analysis implicated collagen-containing extracellular matrix (ECM) pathways. Lysyl oxidase (LOX), a key ECM cross-linking enzyme, was identified as a lead candidate. LOX and its family member LOXL1 were consistently downregulated in BrM tissues and plasma EVs. Single-cell analysis revealed decreased LOX expression specifically in BrM-associated fibroblasts, which showed suppressed ECM-related pathways. In vitro experiments supported a PI3K/AKT-LOX-ECM regulatory axis. Plasma EV-derived LOX demonstrated strong diagnostic performance in the independent cohort, with an AUC of 0.786 (95% CI 0.713iated fi. Our study establishes plasma EV-derived LOX as a promising non-invasive biomarker for LUAD-BrM through a comprehensive multi-omics validation strategy. We propose a model wherein downregulation of LOX, potentially driven by PI3K/AKT signaling in tumor-associated fibroblasts, contributes to ECM degradation and may promote brain-tropic metastasis. This finding offers new insights for risk stratification and timely intervention in LUAD patients.

Chronic airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis, impose a significant global health burden. A central unifying feature of these diseases is redox imbalance, which is characterized by an excess of reactive oxygen and nitrogen species (ROS/RNS) that overwhelms the body’s antioxidant defenses, causing cellular dysfunction, inflammation, and tissue damage. Physiological ROS/RNS are essential for immune regulation and transcriptional control, but chronic oxidative stress disrupts these processes, driving disease progression. In asthma, eosinophil- and epithelial-derived ROS worsen airway hyperresponsiveness, induce mucus overproduction, and reduce steroid effects. COPD involves neutrophil-dominated inflammation, mitochondrial dysfunction, protease- and oxidant-mediated extracellular matrix degradation, and accelerated senescence. Bronchiectasis features persistent neutrophilic oxidative injury, microbial colonization, impaired mucociliary clearance, and progressive airway destruction. Exogenous oxidants, cigarette smoke, biomass fuels, pollutants, and pathogens further burden antioxidant systems, including superoxide dismutases, catalase, glutathione peroxidase, and Nrf2-regulated pathways. Redox dysregulation also contributes to post-COVID sequelae, promoting ongoing airway inflammation, fibrosis, and systemic complications. Therapeutic strategies targeting redox imbalance, mainly thiol-based antioxidants, Nrf2 activators, NADPH oxidase inhibitors, and mitochondria-targeted antioxidants, show mechanistic promise but face challenges in specificity, bioavailability, and clinical translation. Advancing precision redox medicine requires biomarker-guided patient stratification, high-resolution redox proteomics, single-cell and organoid models, and spatial imaging to identify disease-specific redox endotypes. Modulating pathological oxidative stress while preserving physiological signaling offers a novel avenue to improve outcomes. Understanding redox biology in airway disease highlights the potential of precision antioxidant strategies as adjuncts to conventional therapies, representing a paradigm shift in managing chronic airway disorders.

Light-emitting diode (LED) therapy is a promising non-invasive approach for tendinopathy, yet clinical adoption is hindered by heterogeneous treatment parameters and undefined molecular mechanisms. The role of the Interleukin (IL)-6/signal transducer and activator of transcription 3(STAT3) signaling axis in LED-mediated tendon repair remains unexplored. This study aimed to screen effective LED parameters for mitigating tendinopathy by evaluating their effects on inflammation and extracellular matrix (ECM) synthesis in tenocytes, to preliminarily explore the role of the IL-6/STAT3 axis, and to validate the anti-inflammatory and pro-repair effects of selected parameters in a rodent model. Tenocytes from 8 week-old male Sprague-Dawley rat's Achilles's tendon were cultured and stimulated with IL-1β to model inflammatory tendinopathy. Cells underwent LED irradiation at varying wavelengths (625nm, 810nm, 940nm) and energy densities. Cell viability was assessed via CCK-8 assay; expression of inflammatory markers (IL-6, Substance P (SP)), ECM components (type I collagen (COL1), type III collagen (COL3), and lubricin (PRG4) was quantified using qPCR, Western blot, and immunofluorescence to determine optimal LED parameters. STAT3 inhibition was applied to IL-1β-stimulated cells before LED treatment to probe STAT3's role. In vivo, collagenase-I was injected into rat Achilles tendons to induce tendinopathy, followed by LED therapy. Pain thresholds were measured using von Frey filaments, tendon histopathology was evaluated via Hematoxylin and Eosin (H&E) staining and modified Bonar scoring, and expression of COL1, COL3, IL-6, SP, and PRG4 was assessed by immunofluorescence and immunohistochemistry. LED irradiation at 625nm/52.8J/cm2 markedly reduced IL-1β-induced IL-6 and SP expression, while 810nm/39.6J/cm2 and 940nm/26.4J/cm2 enhanced COL1 synthesis without affecting COL3 or PRG4 levels. Mechanistically, LED therapy restored IL-1β-suppressed STAT3 activation, an effect abrogated by STAT3 inhibition. In vivo, 625nm and 940nm LED treatments alleviated mechanical hyperalgesia in collagenase-I-induced tendinopathy, with 625nm showing superior efficacy in reducing IL-6 and SP, enhancing COL1 deposition, and restoring tendon architecture. IL-1β disrupts tendon homeostasis by driving inflammation and ECM degradation. LED therapy at 625nm/52.8J/cm2 mitigates these effects, potentially by restoring STAT3 activity within the IL-6/STAT3 axis, thereby suppressing IL-6 expression.This provides a mechanistic foundation for refining LED-based tendinopathy treatments.

Osteoarthritis (OA) is a severe chronic inflammatory disorder with limited treatment options. Naringin (nar) has been shown to protect against OA; however, its mechanisms of action on OA remain poorly understood. This study aims to investigate the molecular mechanism of nar in treating OA via network pharmacology and experiments. Differentially expressed genes (DEGs) were identified using GSE283079 dataset. Protein-protein interaction (PPI) network was constructed using STRING database, and protein interactions were analyzed. Network pharmacology was employed to investigate the molecular interaction network influenced by nar in OA, and molecular docking was applied to predict the binding interactions between nar and core genes. The OA mouse models were constructed using anterior cruciate ligament transection (ACLT) to explore the action of nar in vivo. The OA damage was examined using Hematoxylin and Eosin (HE) and Safranin-O/Fast Green staining, along with Osteoarthritis Research Society International (OARSI) scoring for quantitative histopathological evaluation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive rate and inflammation factor (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), and reactive oxygen species (ROS) levels were detected using corresponding assay kits. The protein expression was analyzed using western blot. Cell viability and cell apoptosis were examined using cell counting kit 8 (CCK8) assay kit and flow cytometry assays. In GSE283079 dataset, the up-regulation of DEGs was enriched in immune response activation, cartilage development, collagen metabolic process, and leukocyte proliferation. Additionally, matrix metalloproteinase 13 (MMP13), MMP1, and phospholipase A2 group IIA (PLA2G2A) may be the core genes for nar-protected OA. The binding energy of nar and MMP13 was strongest. In vivo OA models, nar mitigated OA progression and reduced OARSI scores. Mechanistically, nar suppressed cell apoptosis, inflammation factor productions, extracellular matrix (ECM) degradation, and ROS production via decreasing MMP13. Nar alleviates OA malignant progression via reducing MMP13.

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies.

FGD1 is an X-linked gene and acts as a guanine nucleotide exchange factor that activates guanosine triphosphatase Cdc42 and influences cell cycle progression, cell morphology, motility, and extracellular matrix degradation. In this study, we aim to understand FGD1 function in melanoma to better understand the correlation between poor survival and high FGD1 expression identified in The Cancer Genome Atlas messenger RNA data, especially in patients with BRAF mutations. FGD1 knockdown in BRAF V600E-mutated melanoma cell lines reduces cell proliferation and induces secondary resistance to BRAF inhibition, while increasing sensitivity to p21-activated kinase inhibition. Markedly, when FGD1 knockdown becomes ineffective, resistant cells not only restore endogenous FGD1 expression but also exhibit upregulation of epidermal growth factor receptor and phospho-p21-activated kinase, both known markers of BRAF inhibition resistance, highlighting a shift toward an adaptive resistance phenotype. Furthermore, we show that secondary resistance induced by prolonged exposure of melanoma cells to BRAF inhibitor is associated with reduced FGD1 levels. These findings highlight the importance of FGD1 in melanoma progression and the acquisition of secondary resistance, positioning the FGD1-mediated signaling pathway as a putative therapeutic target.

Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE-/- mice with pneumonia-complicated atherosclerosis. The FRP, integrating photoacoustic and fluorescence imaging modalities, enabled comprehensive longitudinal monitoring of plaque furin dynamics both in vitro and in vivo. Notably, dexamethasone treatment effectively reduced plaque furin content, demonstrating the reversibility of this inflammatory response. Histopathological analysis confirmed that furin upregulation correlated with increased plaque inflammation, extracellular matrix degradation, and necrotic core expansion. These findings establish in vivo furin imaging as a valuable approach for elucidating the mechanistic links between systemic inflammation and plaque vulnerability and for evaluating therapeutic interventions aimed at plaque stabilization.

The tumour microenvironment (TME) is a complex dynamic ecosystem where cancer cells, immune responses, and the extracellular matrix (ECM) engage in a delicate battle for dominance. Capturing this interesting interplay within a mathematically tractable yet biologically meaningful framework remains a key challenge. In this work, we construct and analyse a novel three-dimensional ODE model that describes the interaction between cancer cells, immune response, and ECM and reveals an interestingly rich dynamical landscape characterized by multiple bifurcation phenomena, deterministic chaos, and stochastic transitions. Through rigorous bifurcation analysis, we uncover transcritical, saddle-node, cusp, and Bogdanov–Takens bifurcations, each portraying critical transitions between distinct tumour states. The system further shows deterministic chaos, illustrating how intrinsic nonlinear interaction can induce unpredictable tumour behaviour even in the absence of external perturbations. Afterward we investigate how random environmental effects modulate tumour persistence or extinction through stochastic sensitivity by incorporating random fluctuations into biologically relevant parameters. Our findings demonstrate that ECM degradation, coupled with immune suppression, orchestrates a key mechanism driving tumour persistence and escape. Theoretically and biologically, our study provides a unified framework that links deterministic and stochastic processes to better understand and control cancer progression.

Mitochondria are increasingly recognized as central regulators of skin health and aging, providing ATP and coordinating redox signaling, mitophagy, and cell fate decisions. In cutaneous tissues, mitochondrial integrity sustains fibroblast-driven collagen synthesis, keratinocyte proliferation, melanocyte homeostasis, and efficient wound repair. With advancing age and cumulative ultraviolet exposure, mitochondria accumulate hallmark defects. Mitochondrial DNA mutations and deletions, impaired oxidative phosphorylation, excessive reactive oxygen species production, diminished mitophagy and biogenesis, disrupted fission-fusion dynamics, NAD⁺ decline, and sirtuin dysregulation all converge to undermine energy metabolism, amplify inflammatory signaling, and accelerate fibroblast senescence, extracellular matrix degradation, pigmentary changes, and delayed wound healing. Recent research also highlights weakened antioxidant defenses and extracellular vesicle-mediated propagation of mitochondrial stress across the cutaneous microenvironment, underscoring the organelle's central role in skin aging. Against this mechanistic backdrop, mitochondria-targeted interventions are emerging as promising therapeutic strategies. Extracellular vesicles loaded with NAD⁺ precursors, antioxidant enzymes, or mitophagy stimulators show preclinical efficacy in restoring bioenergetics and accelerating wound closure. Mitochondria-directed antioxidants such as melatonin and coenzyme Q10, NAD⁺ boosters and sirtuin activators, red and near-infrared photobiomodulation, and NRF2-based redox reprogramming each enhance mitochondrial homeostasis while improving collagen synthesis, pigmentation balance, and re-epithelialization. Early translational and clinical studies indicate that these approaches protect against UV-induced mitochondrial DNA damage, reduce oxidative stress, and improve cutaneous structure and function. Collectively, these findings position mitochondria as a modifiable hub for cutaneous aging and wound repair, and highlight the potential of integrated metabolic, antioxidant, and vesicle-based approaches to transform dermatologic anti-aging and wound-care interventions.