Search Results (29,021)

Critical-sized bone defects pose significant challenges in orthopedic surgery. The introduction of 3D printing technology in bone grafting offers a promising solution by creating customized grafts that mimic the natural bone structure. This study aimed to reconstruct long-segment bone defects in the rabbit radius using a 3D-printed material composed of hydroxyapatite (HAP) and poly(lactide-co-glycolide) (PLGA), referred to as ALBO-OS, and to evaluate its potential to support bone healing without the use of stem cells or growth factors. Six rabbits underwent computed tomography scanning to create patient-specific 3D models of the radius. Custom-designed ALBO-OS implants were 3D-printed and used to fill segmental defects corresponding to one-third of the bone length in each rabbit, created by osteotomy. Over a 12-week observation period, graft integration, osteointegration, and overall bone regeneration were assessed through histological and histomorphometric analyses. The implanted scaffolds demonstrated encouraging bone healing, with significant bone regeneration observed within the defect areas. Histological evaluation revealed significant new bone formation and vascularization, with minimal inflammatory response. The findings demonstrated the potential of 3D-printed HAP/PLGA-based materials as a promising strategy for the reconstruction of large bone defects, eliminating the need for exogenous biological agents. Full article

Background: Frailty has been linked with systemic inflammation in elderly oncology patients. In this paper, we report the results of an analysis evaluating the association between blood cell biomarkers of inflammation and frailty in patients with operable non-small-cell lung cancer (NSCLC). Methods: A retrospective analysis was performed on patients undergoing surgery for NSCLC between March 2022 and March 2023. Frailty was assessed using the modified Frailty Index-5 (mFI-5) and 11 (mFI-11). Inflammation was evaluated using the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune–inflammation index (SII), and systemic immune–inflammation response index (SIRI), all calculated from preoperative assessments. Results: In this sample of surgical NSCLC patients (n = 106), frailty prevalence was 29.2% with mFI-11 and 17% with mFI-5. The log of the neutrophil-to-lymphocyte ratio (logNLR) emerged as the most significant predictor of frailty (OR of 3.13, 95% CI: 1.12–9.09, p = 0.03 for mFI-11 and 3.82, 95% CI: 1.28–11.11, p = 0.02 for FI-5). The platelet-to-lymphocyte ratio (PLR) was predictive only in the model assessing mFI-5. Furthermore, both the NLR and PLR showed an inverse linear correlation with frailty severity, a finding that remained consistent regardless of age, gender, disease stage, nutrition status, or comorbidity burden. Conclusions: Frail patients with operable NSCLC exhibit distinct inflammatory response patterns compared with those observed in non-frail lung cancer patients. Using these biomarkers could help identify patients suitable for preoperative interventions that could improve their postoperative course. However, further studies are needed to explore these preliminary findings prospectively and to understand the causal relationship between the observed association with frailty status and severity. Full article

A muscle biopsy (MB) is an important tool to help differentiate idiopathic inflammatory myopathies (IIMs) from hereditary muscular diseases (HMDs). The usefulness of immunohistochemical stains of the major histocompatibility complex class I and the membrane attack complex are controversial, as both may be identified in some HMDs. More sensitive markers of IIMs have recently been used, such as myxovirus resistance A (MxA), a type I interferon-inducible protein. We selected skeletal MB samples from 81 patients diagnosed with IIM and HMD harbouring overt inflammatory infiltrates on their MBs in the period between March 2022 and September 2024. Two groups were identified: the IIM group (46 cases) and the HMD group (35 cases). We characterized and compared the patterns of MxA protein expression among the two groups. In the IIM group, positive sarcoplasmic MxA expression was detected on the myofibres of 10 patients (24%), among whom were eight dermatomyositis patients. In the HMD group, we did not identify any sarcoplasmic positivity. However, five patients (14%) showed positive labelling restricted to the sarcolemmal membrane, including non-necrotic or regenerating fibres. Our study demonstrates the value of MxA for increasing dermatomyositis diagnostic accuracy and suggests the potential role of interferon type I in the pathophysiology of HMD. Full article

Background/Objectives: Retinoblastoma represents the most common intraocular malignancy in childhood; however, the clinical applicability of mitomycin C (MMC) is restricted by dose-dependent ocular toxicity. Consequently, the development of pharmacological strategies that sensitize tumor cells to MMC while allowing dose reduction remains an unmet therapeutic objective. In this context, quercetin, a bioactive flavonoid with pleiotropic anticancer properties, has emerged as a potential chemosensitizing agent. Methods: Human retinoblastoma cell lines Y79 and WERI-Rb1 were exposed to MMC and quercetin, administered either individually or in fixed-ratio combinations. Cytotoxic responses were quantified through dose–response modeling and IC₅₀ determination following 24 and 48 h of treatment. Drug–drug interactions were quantitatively characterized using the Chou–Talalay combination index (CI) approach and isobologram analysis. Cell cycle distribution was assessed by propidium iodide (PI)-based flow cytometric analysis to evaluate treatment-associated alterations in cell cycle progression. Apoptotic cell death was assessed by Annexin V-FITC/PI flow cytometry, while transcriptional modulation of genes associated with apoptosis, cell cycle regulation, and oxidative stress (BAX, BCL-2, TP53, CASP3, CDKN1A, and HMOX1) was evaluated by qRT-PCR. Modulation of tumor-supportive signaling was examined by measuring VEGF and IL-6 secretion. Translational relevance was further investigated using a three-dimensional (3D) tumor spheroid model, and the functional contribution of reactive oxygen species (ROS) was interrogated through N-acetyl-L-cysteine (NAC) rescue experiments. Results: Quercetin significantly enhanced the cytotoxic activity of MMC in both retinoblastoma cell lines, with CI values below 1 across IC₅₀–IC₉₀ effect levels, indicating a synergistic pharmacological interaction. PI–FACS analysis revealed that combined MMC and quercetin treatment induced a pronounced accumulation of cells in the G2/M phase, consistent with cell cycle arrest, with a more marked effect observed in Y79 cells compared with WERI-Rb1 cells. Combination treatment resulted in a pronounced increase in apoptotic cell populations compared with single-agent exposure and triggered a coordinated pro-apoptotic transcriptional response, characterized by increased expression of BAX, TP53, CASP3, CDKN1A, and HMOX1, alongside suppression of BCL-2 and a marked shift in the BAX/BCL-2 ratio. Concurrently, VEGF and IL-6 secretion were significantly reduced, reflecting attenuation of pro-angiogenic and pro-inflammatory signaling. Notably, synergistic cytotoxicity was maintained in 3D tumor spheroids, where combined treatment induced spheroid shrinkage, architectural disruption, and reduced viability. NAC pretreatment diminished ROS accumulation and partially restored cell viability, indicating that oxidative stress contributes to, but does not solely account for, the observed synergistic cytotoxic effect. Conclusions: Collectively, these findings indicate that quercetin appears to function as an effective chemosensitizing adjuvant to MMC in retinoblastoma models, through transcriptional changes consistent with p53-associated apoptotic signaling at the transcriptional level, G2/M cell cycle arrest, and partial involvement of ROS-related cellular stress responses, along with suppression of tumor-supportive signaling pathways. The preservation of synergistic activity in 3D tumor spheroids supports the potential preclinical relevance of this combination. However, these findings are based on transcriptional and phenotypic analyses and should be interpreted as hypothesis-generating, requiring further validation through protein-level and in vivo studies before translational application. Full article

Background: The optimal timing of adjuvant chemotherapy after cytoreductive surgery in epithelial ovarian cancer remains uncertain, and perioperative wound-healing responses may transiently create a pro-tumorigenic and drug-resistant microenvironment. This study aimed to characterize time-dependent wound-induced transcriptomic alterations and to identify pharmacologic agents capable of reversing these responses. Methods: An ID8 murine ovarian cancer model was used to compare no treatment, anesthesia alone, and anesthesia plus surgical wounding mimicking futile laparotomy. Tumors were collected at baseline, 1 day (T1), 1 week (T2), and 2 weeks (T3) after intervention. RNA sequencing was performed, and wound-specific differentially expressed genes (WsDEGs) were defined by excluding anesthesia- and progression-related signatures. Functional enrichment analyses were conducted, followed by transcriptome-based drug repurposing using the REMEDY platform to identify compounds predicted to reverse wound-induced gene expression profiles. Results: Surgical wounding significantly increased tumor burden at T1. Transcriptomic analyses revealed distinct, time-dependent wound-associated programs. At T1, WsDEGs were enriched in inflammatory signaling, coagulation, angiogenesis, and immune cell migration, with Vorinostat and Homoharringtonine identified as top candidates to counteract these signatures. At T2, pathways related to cell survival, adhesion, and morphogenesis predominated, with LY-2090314, Artesunate, and Birinapant emerging as potential modulators. At T3, cell-cycle regulation and lipid metabolic pathways were dominant, and Fulvestrant, Atorvastatin, Imatinib, and ABT-737 were predicted to inhibit these processes. Conclusions: Perioperative surgical wounding induces dynamic, stage-specific transcriptomic programs that may promote ovarian cancer progression and alter drug responsiveness. These findings support time-adapted perioperative pharmacologic strategies to optimize postoperative cancer therapy. Full article

Periodontitis (PD) and atrial fibrillation (AF) are two prevalent chronic conditions with substantial public health burdens worldwide. While traditionally studied separately, increasing evidence reveals a complex interplay between PD and AF, mediated primarily by shared inflammatory and immune mechanisms. Chronic periodontal inflammation can trigger systemic immune activation, leading to atrial structural remodeling, fibrosis, and electrical disturbances that predispose individuals to AF. Observational and longitudinal studies consistently demonstrate a higher incidence and recurrence of AF in patients with moderate to severe PD, independent of established cardiovascular risk factors. Key periodontal pathogens, especially Porphyromonas gingivalis, and altered immune cell profiles are implicated in this association, further supported by genetic analyses revealing common molecular pathways. Mechanistic insights from experimental models highlight the role of inflammation-related atrial fibrosis and immune dysregulation as critical drivers linking oral disease to arrhythmogenesis. Additionally, better oral hygiene practices and periodontal treatment have been associated with a reduced risk of AF, suggesting modifiable intervention potential. This review synthesizes current clinical, epidemiological, molecular, and experimental evidence to elucidate the PD–AF relationship, emphasizing periodontal health as a promising target in cardiovascular disease prevention strategies. Full article

Background: Oral diseases such as periodontitis, dental infections, and oral dysbiosis have been increasingly associated with systemic conditions. Emerging evidence suggests a potential relationship between oral health and neurological disorders, including brain abscesses, structural brain alterations, and gliomas. However, the strength and mechanisms of these associations remain incompletely understood. Objective: To systematically review clinical, neuroimaging, genetic, and mechanistic evidence linking oral diseases with brain pathologies. Methods: A systematic literature search was conducted in PubMed, Scopus, Web of Science, and EBSCO, with complementary screening of SciELO, Redalyc, and LILACS databases. Studies evaluating associations between oral diseases (periodontitis, dental infections, caries, or oral microbiota alterations) and neurological outcomes were considered. Eligible study designs included observational clinical studies, Mendelian randomization analyses, neuroimaging studies, and experimental investigations. Seventeen studies met the inclusion criteria. Due to the substantial heterogeneity in study designs, outcomes, and effect metrics, quantitative meta-analysis was not feasible. Findings were therefore synthesized using a structured narrative approach following PRISMA guidelines. Results: Clinical studies consistently identified odontogenic infections as a relevant source of brain abscesses, frequently originating from chronic or clinically silent dental foci. Neuroimaging and genetic studies reported associations between poor oral health indicators and structural brain alterations, including reduced cortical thickness and white matter abnormalities. Experimental investigations suggested potential biological mechanisms involving microbial dissemination, systemic inflammation, and immune modulation. Virulence factors from Porphyromonas gingivalis have been shown to induce inflammatory signaling pathways and immune checkpoint activation in glioma cells. Conclusions: The current evidence suggests a possible association between oral diseases and several brain pathologies. Although causality cannot be established, the findings highlight the importance of oral health as a potentially modifiable factor relevant to neurological health. Further longitudinal and mechanistic studies are required to clarify these relationships. Full article

Atherosclerosis, the leading global cause of death, is a chronic inflammatory vascular disease with higher prevalence and earlier onset in men than in women. This study aims to investigate sex differences in the atherogenic endothelial phenotype during early atherosclerosis processes by providing the first comprehensive analysis of hormone-independent responses in human umbilical vein endothelial cells (HUVECs) from opposite-sex twins. HUVECs underwent pro-inflammatory stimulation with TNF-α and supernatant from activated pro-inflammatory THP-1 cells, revealing distinct sex-specific patterns: mRNA expression of focal adhesion proteins talin-I, vinculin, FAK, and α1-actinin increased significantly only in male cells, while paxillin showed elevated mRNA and protein levels in both sexes. Male HUVECs exhibited stronger induction of cell adhesion molecule VCAM-1, pro-inflammatory cytokine IL-1β, and proangiogenic factors Flt-3L, G-CSF, and PDGF-AA, whereas IL-22 secretion was exclusively upregulated in female cells. These sex differences in levels of focal adhesion, adhesion molecules, and cytokine profiles uncover the mechanistic backgrounds of the atherogenic endothelial phenotype, independent of systemic hormones. The findings emphasize cellular sex as a critical biological variable in early atherosclerosis and vascular inflammation. Full article

Background: Ulcerative colitis (UC) is an intestinal disease characterized by long-term inflammation. Circadian rhythm disorder (CRD) affects various biological activities and has been linked to several diseases, including UC. This study aimed to investigate the role and significance of CRD in UC. Methods: Bulk RNA-seq data from five independent UC cohorts were obtained from the Gene Expression Omnibus (GEO) database and integrated into a single dataset. The dataset underwent differential analysis to identify differentially expressed genes (DEGs) in association with CRD. Expression levels and pathway enrichment of CRD genes were analyzed, and signature genes were identified using machine learning algorithms. Based on these signature genes, a UC risk prediction model and CRD-related molecular subtypes were established. Furthermore, single-cell RNA-seq data of UC were analyzed to discuss the key role of CRD and signature genes in the UC microenvironment. RT-PCR analysis was employed to validate the expression levels of the identified signature genes. Results: 247 DEGs associated with CRD in UC were identified (referred to as CRD-DEGs). Gene set enrichment analysis (GSEA) revealed a strong association between CRD and inflammation, as well as immune cell infiltration in UC. This association potentially impacts intestinal fibrosis. A comparison of three machine learning algorithms (Lasso, SVM-RFE, and Random Forest) resulted in the identification of 12 signature genes. A UC risk prediction model and two UC CRD subtypes were developed using these genes. Among them, STXBP1 was identified by all three machine learning algorithms and was further analyzed. STXBP1 was predominantly enriched in pathways related to inflammatory response. Elevated levels of STXBP1 are mainly caused by reduced levels of methylation of its gene promoter. RT-PCR confirmed elevated expression of certain genes in mouse UC models. Conclusions: This study is the first to establish a strong association between CRD and the onset of UC. The newly developed UC nomogram based on CRD demonstrated high predictive accuracy, although further clinical validation is required. Understanding the intrinsic relationship between CRD and UC enhances our understanding of the potential pathogenesis of UC. This study introduces novel ideas and methods for early diagnosis, treatment, and prognosis of UC. Full article

Glaucoma, characterized by progressive retinal ganglion cell degeneration and optic nerve damage, is the leading cause of irreversible blindness worldwide. Multiple risk factors influence the pathogenesis and progression of glaucoma. Food-derived bioactive components have emerged as a new area of interest to overcome the limitations of current standard treatments due to their antioxidant and anti-inflammatory activities and multi-target mechanisms. In this context, various plant-derived foods, such as Lycium barbarum, Ganoderma lucidum, Cryptotanshinone, Scutellaria baicalensis, Silybum marianum, Astragalus membranaceus, Ginkgo biloba, Panax ginseng, Crocus sativus, and resveratrol, have shown potential mechanisms for treating glaucoma. These bioactive components may address oxidative damage, neuroinflammation, and elevated intraocular pressure, which may be due to the modulation of multiple signaling pathways, including JAK2/STAT3, PI3K/AKT, MEK/ERK/CREB, cAMP/PKA/CREB, and others. However, further clinical trials are needed to validate dosage, bioavailability, and long-term safety. This review highlights the potential of bioactive components from plant-derived foods, offering a reference for further investigation into their effects on glaucoma. Full article

This study provides a comparative evaluation of two Salvia species, the widely cultivated Salvia sclarea L. and the comparatively underexplored wild species Salvia pratensis L., integrating phytochemical profiling, chemical safety assessment, and biological activity investigation. Dried hydroethanolic extracts and essential oils obtained from aerial parts were analysed. HPLC–PDA analysis revealed distinct phenolic acid profiles, with S. sclarea characterized by higher levels of rosmarinic and protocatechuic acids, whereas S. pratensis contained greater amounts of hydroxycinnamic acids such as caffeic, p-coumaric, and ferulic acids. The total phenolic content was higher in S. pratensis (79.22 mg GAE/g dry extract) than in S. sclarea (52.50 mg GAE/g). GC–MS analysis showed that the essential oil of S. sclarea was dominated by oxygenated monoterpenes, mainly linalyl acetate and linalool, while S. pratensis exhibited a linalool-rich profile accompanied by sesquiterpene derivatives. Chemical safety assessment indicated minimal contamination, with pesticide residues detected only in S. sclarea at levels below regulatory limits and low concentrations of cadmium and lead in both species. The extracts showed strong antioxidant activity (DPPH IC₅₀ values of 6.67 µg/mL for S. sclarea and 3.16 µg/mL for S. pratensis) and moderate broad-spectrum antimicrobial activity (MIC 312.5–2500 µg/mL). In vitro assays on HEK 293 and HaCaT cells confirmed low cytotoxicity, with no evidence of membrane damage or pro-inflammatory effects. Overall, the results highlight the significant bioactive potential of the less studied S. pratensis, demonstrating that this wild species represents a promising alternative source of natural antioxidant and antimicrobial compounds comparable to the widely cultivated S. sclarea. Full article

Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho-γ-pyrone (aS)-fonsecinones B and D (1 and 2) and 14 known compounds (3–16) from the deep-sea-derived fungus Aspergillus niger 3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 (10) as the most potent candidate. Compound 10 significantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed that 10 targets NOS2 to modulate Alzheimer’s disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated that 10 occupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally, 10 ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compound 10 as a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD. Full article

Sonchus oleraceus L., a member of the Asteraceae family native to Eurasia, is a herbaceous plant whose young stems and leaves are consumed globally as a medicinal and edible wild vegetable; it is rich in flavonoids and exhibits various pharmacological activities, including anti-inflammatory and anti-tumor effects. This study optimized the extraction process of flavonoids from Xinjiang S. oleraceus using response surface methodology and evaluated the anti-inflammatory activity of luteoloside in vitro. Based on single-factor experiments and Box–Behnken design, the effects of ethanol concentration, extraction time, solid-to-liquid ratio, and extraction temperature on flavonoid yield were investigated. The optimal extraction conditions were determined as ethanol concentration 62%, extraction time 30 min, solid-to-liquid ratio 1:91 g/mL, and extraction temperature 64 °C, with a flavonoid yield of 21.64 mg/g. After purification via polyamide column chromatography, the luteoloside content was determined by HPLC to be 44.06 μg/g. Cytotoxicity assays revealed that a luteoloside concentration of 100 μmol/L reduced the viability of Oryctolagus cuniculus colon epithelial cells to approximately 80%. ELISA results demonstrated that luteoloside significantly inhibited the release of pro-inflammatory factors, including TNF-α, while promoting the expression of the anti-inflammatory factor IL-10. These findings indicate that luteoloside effectively alleviates LPS-induced cellular inflammation. Full article

Background: Severe lung compromise from COVID-19, ARDS, and recently AH3N2 can progress to life-threatening hypoxia. Past experience led to standardized protocols that assumed similarity to SARS-CoV. Methods: COVID-19 pathophysiology and histopathological lung biopsy photomicrographs are analyzed. Results: Pneumolysis is defined as progressive alveolar–capillary destruction resulting from SARS-CoV-2 attack on pneumocytes. In the final stages preceding pneumolysis, molecular mechanisms in the lungs include apoptosis in alveolar epithelial type I and II cells, compromising alveolar regeneration, and necrosis, resulting in leakage of intracellular contents and amplifying inflammation. Pyroptosis, driven by inflammasome activity, further disrupts alveolar integrity in ARDS. Histopathological findings include Masson bodies, alveolar-coating cells with nuclear atypia, reactive pneumocytes and reparative fibrosis, intra-alveolar hemorrhage, moderate inflammatory infiltrates and abscesses, microthrombi, hyaline membrane remnants, and emphysema. The three theoretical pathophysiological stages of progressive hypoxemia (silent hypoxemia, gasping, and death zone) are shown. Conclusions: Silent hypoxemia rapidly progresses to critical hypoxemia. This progression results from progressive pneumolysis, inflammation, immune overexpression, autoimmunity, and HAPE-type edema, leading to acute pulmonary insufficiency. Long-lasting COVID-19 can result in fibrosis and, as a compensatory mechanism, polierythrocythemia. The proposed treatment (based on tolerance to hypoxia and the hemoglobin factor) includes prompt oxygen administration, control of inflammatory and immune responses, antibiotics, rehydration, erythropoietin and platelet aggregation inhibitors. Full article

Bovine viral diarrhea virus (BVDV), a globally persistent pathogen, causes bovine viral diarrhea-mucosal disease (BVD-MD), a contagious bovine disease posing significant pressures on both public health and economic development. Baicalin (BA), a flavonoid derived from Scutellaria baicalensis, exhibits broad antiviral activities but suffers from poor aqueous solubility and low bioavailability, limiting its therapeutic potential against BVDV. To address this limitation, we developed BA-loaded poly (ethylene gly-col)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (BA-PEG-PLGA NPs). While autophagy and NLRP3 inflammasome activation have been individually implicated in viral pathogenesis, their functional crosstalk during BVDV infection remains uncharacterized. Herein, we evaluated the antiviral efficacy of BA-PEG-PLGA NPs through integrated in vitro and in vivo experiments. We employed quantitative polymerase chain reaction (qPCR), transcriptome sequencing, Western blot analysis, immunofluorescence microscopy, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) to investigate the mechanisms by which BA and BA-PEG-PLGA NPs combat bovine viral diarrhea virus (BVDV) infection. We found that both free BA and BA-PEG-PLGA NPs effectively attenuated BVDV replication in vitro and in vivo; notably, the nano-formulation exhibited superior efficacy. Mechanistically, BA and its nano-formulation restored autophagy homeostasis, suppressed ROS overproduction, and blocked NLRP3 inflammasome activation and pyroptotic cell death effects comparable to the specific NLRP3 inhibitor MCC950. These findings establish the autophagy–NLRP3/pyroptosis axis as a critical pathogenic mechanism in BVDV infection and reveal that nano-formulated baicalin represents an antiviral strategy by coordinately targeting this axis. This work not only provides a translatable nanomedicine approach for BVDV control but also expands the mechanistic understanding of flavonoid-based interventions in viral inflammatory diseases. Full article