Search Results (23,069)

This study investigated the protective effects of DBD against Staphylococcus aureus (S. aureus)-induced mastitis in mice and explored whether these effects were associated with gut microbiota alterations, blood–milk barrier integrity, and inflammatory signaling. A lactating mouse model of mastitis was established, and the effects of DBD were evaluated using HPLC, histopathological analysis, ELISA, qRT-PCR, Western blotting, immunofluorescence, and 16S rRNA sequencing. The results showed that DBD significantly reduced bacterial loads in mammary tissues, decreased the expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and alleviated inflammatory cell infiltration and tissue damage. Moreover, DBD upregulated the expression of tight junction proteins and improved the integrity of the blood–milk barrier. DBD treatment was also associated with alterations in gut microbiota composition, as reflected by changes in the relative abundance of several bacterial taxa. In addition, DBD inhibited the activation of the NF-κB/NLRP3 and MAPK inflammatory signaling pathways. Collectively, these findings indicate that DBD alleviates S. aureus-induced mastitis accompanied by alterations in gut microbiota composition, suppressing inflammatory responses, and repairing the blood–milk barrier, suggesting its potential as a therapeutic agent for mastitis. Full article

Background: Ventral hernias are a common complication following abdominal surgery, occurring in up to 20% of patients after midline laparotomy and as many as 43% of those who undergo orthotopic liver transplantation (OLT). These hernias pose unique challenges due to chronic immunosuppression, impaired wound healing, and the anatomic disruption caused by subcostal and “Mercedes-Benz” incisions. As survival after OLT continues to improve, the need for durable, infection-resistant abdominal wall reconstruction has become increasingly important. Methods: We performed a single-institution retrospective review of all OLT patients undergoing abdominal wall reconstruction by the senior author between June 2014 and April 2026. Our approach emphasizes component separation to reestablish myofascial continuity, biologic onlay reinforcement with human acellular dermal matrix (HADM), and multipoint fixation in a progressive tension pattern. Results: Forty patients (43 encounters) were included. Mean age was 55.7 ± 10.2 years, mean BMI was 31.2 ± 4.9 kg/m², and 60.0% were obese. The majority presented with recurrent hernias (67.4%), and 41.9% had prior mesh in situ. Component separation was performed in all cases, and intraoperative Botox in 18.6%. HADM was used in 83.7% of encounters. At a mean follow-up of 34.0 months, there was 1 hernia recurrence (2.3%). The surgical site occurrence rate was 14.0%, with seroma as the most common complication (9.3%). There were no 30-day mortalities. Conclusions: By integrating biologic and mechanical principles, this reconstructive strategy provides a durable solution for abdominal wall repair in liver transplant recipients. A 2.3% recurrence rate and 14.0% surgical site occurrence rate compare favorably to published benchmarks in the transplant population. Full article

When an individual A is accused of having committed a morally impermissible action X, it is generally accepted that they may invoke three types of defenses to mitigate, or even eliminate, their moral responsibility (or at least the fittingness of blame): justifications, excuses, and exemptions. However, another consideration—one that does not prima facie fall under any of these three types of defenses—also appears capable of influencing moral responsibility: the passage of time. A might argue that, although they did indeed commit the morally impermissible action X, the fact that it occurred twenty years ago partially absolves them from responsibility. This idea, which underlies several legal principles—such as statutes of limitations, rehabilitation, and sentence reduction—raises underexplored philosophical issues. In this paper, we argue that the passage of time does not constitute an autonomous moral defense. Rather, it is morally relevant only insofar as it makes possible certain transformations—including psychological reform, repentance, and processes of moral repair—capable of modifying the normative conditions under which it is appropriate to hold an agent to account. Accordingly, the attenuation of diachronic responsibility is best understood not as a direct consequence of temporal distance itself, but as a consequence of changes in those normative conditions. Full article

Background and Clinical Significance: Choanal atresia is a rare congenital obstruction of the posterior nasal aperture, with an estimated incidence of one in 5000 to one in 8000 live births. Bilateral disease typically presents as a neonatal emergency, whereas unilateral disease is more frequent and may remain undiagnosed for years or decades, presenting in adolescence or adulthood with chronic unilateral nasal obstruction and ipsilateral mucopurulent rhinorrhoea. Optimal surgical management remains debated, particularly with regard to mucosal-flap reconstruction and the choice of postoperative stent. Case Presentation: A 22-year-old male was referred for chronic left-sided nasal obstruction, persistent ipsilateral mucopurulent rhinorrhoea and reduced ipsilateral olfaction. Nasal endoscopy and high-resolution computed tomography demonstrated an isolated, non-syndromic, mixed bony–membranous left choanal atresia. The patient underwent transnasal endoscopic choanoplasty with posterior septectomy and removal of the atretic plate and posterior vomer. An ipsilateral superiorly based septal mucoperichondrial flap was raised first and later transposed over the sphenoid rostrum; following drilling, the contralateral septal mucosa was approached and incised horizontally to generate a superior and an inferior leaflet, which were rotated to cover the corresponding portions of the residual posterior septal ridge. A bioabsorbable mometasone-furoate-eluting sinus implant (PROPEL^®, Medtronic) was deployed across the neo-choana. The follow-up endoscopy at two months demonstrated a widely patent, well-mucosalized neo-choana with complete resolution of symptoms. Conclusions: Transnasal endoscopic posterior septectomy combined with mucosal-flap reconstruction and a bioabsorbable steroid-eluting stent is a technically feasible and biologically rational approach to adult unilateral CA. To our knowledge, this is among the first reports describing the off-label intraoperative use of a PROPEL^® stent in a young adult with isolated unilateral choanal atresia. Full article

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

Background/Objectives: Managing bone diseases demands novel, natural compounds to bypass the heavy side effects of current therapies. Honey is well-known for its therapeutic traits, yet we know very little about how specific floral varieties impact bone tissue. This study confronts this gap by comparing how acacia, chestnut, and coriander honeys drive human osteoblast behavior in vitro. Methods: After mapping the phenolic/flavonoid profiles and antioxidant capacities of these honeys, we tested them on hFOB 1.19 human osteoblasts. We tracked cell migration via scratch assays and validated osteogenic maturation through Alkaline Phosphatase (ALP) activity and Alizarin Red (AR) mineralization over 7 days. Confocal time-lapse imaging with pharmacological inhibitors monitored intracellular calcium dynamics, while gene shifts were analyzed via qRT-PCR. Results: Coriander honey (CH) packed the highest polyphenol levels and antioxidant power. Biologically, while all honeys accelerated scratch closure, CH drove cell motility most potently. Remarkably, a 7-day treatment with these honeys sparked a significant and robust increase in ALP activity and mineralization, surpassing the osteogenic induction observed with standard osteoinductive media. Mechanistically, CH triggered a sharp [Ca²⁺] spike, relying on external calcium entry and IP3-dependent internal release via PLC activation. qRT-PCR confirmed this anabolic shift via OPG and OPN upregulation. Conclusions: Honey exerts pronounced multi-level osteopromotive effects at both the functional and transcriptional levels, tightly linked to its botanical source. Among the variants, coriander honey stands out for its exceptional ability to fast-track osteoblast migration, differentiation, and early mineral deposition. Therefore coriander honey represents a promising in vitro candidate that warrants further preclinical evaluation for bone repair applications. Full article

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Chronic wounds represent a substantial and growing clinical burden, yet durable healing remains difficult to achieve in a large proportion of patients. The skin microbiome plays a central role in this challenge: in healthy tissue, resident microorganisms support barrier integrity and calibrate immune responses, whereas in chronic wounds, community disruption—often combined with persistent biofilm formation—drives non-resolving inflammation, impairs re-epithelialisation, and increases antimicrobial tolerance. As antibiotic resistance escalates, these features strengthen the rationale for microbiome-directed strategies that target wound ecology while reducing reliance on conventional antimicrobials. Current evidence is still dominated by mechanistic and preclinical studies, with only early clinical signals for selected approaches; therefore, next-generation probiotics, including Lactiplantibacillus/Lactobacillus spp., as well as defined prebiotic and postbiotic formulations, should be interpreted as promising adjuncts rather than clinically established therapies. Causal mechanisms, optimal formulations, reproducibility, and patient-level determinants of response remain insufficiently defined, representing a critical knowledge gap that limits translation. Here, we synthesise current evidence linking microbial ecology to key wound-healing pathways and propose a precision framework that integrates metagenomics, transcriptomics, metabolomics, and spatial profiling to map host–microbe interactions, identify predictive biomarkers, and guide stratified therapy. We further highlight combinatorial approaches pairing ecological engineering with biofilm-disruptive materials and immune-modulatory molecules. Realising the potential of these interventions will require mechanism-resolved clinical trials, standardised outcome frameworks, and patient stratification tools—advances that could improve chronic wound management while reducing selective pressure for antimicrobial resistance. Full article

The development of biocompatible materials has gained traction due to the increasing clinical demands for customizable and functional medical devices. Chitosan, a deacetylated derivative of chitin, is a naturally occurring biopolymer with strong antimicrobial properties, immunocompatibility, and structural adaptability, making it a promising candidate for biomedical applications. Through mechanisms such as crosslinking, ionic bonding, gas formation, and UV radiation, the mechanical properties and stimulus responses of chitosan-based hydrogels can be tailored for drug delivery at specific sites or under specific pH, light, or electrical conditions. Beyond drug delivery, chitosan hydrogels have shown considerable potential for vascular tissue repair. The porous structure of chitosan allows patient specific vascular scaffolding to be created that promotes the recovery rate veins and stenting procedures. Thermally sensitive hydrogels can deliver drugs to target regions to further assist in vascular healing. Furthermore, recent developments with composite polymers and coatings engineered to self-assemble within veins provide scaffolds for vascular tissue growth. This manuscript reviews chitosan hydrogel fabrication methods and their corresponding materials properties, with particular emphasis on drug delivery to vascular tissues. Furthermore, relevant findings from clinical trials are summarized to support the potential of chitosan hydrogels for future clinical use. Challenges of chitosan hydrogels, such as insufficient mechanical strength, high degradation rates, and complex manufacturing, remain as areas for research break-through. Full article

Background and Objectives: Seroma formation is the most common postoperative complication following mastectomy and axillary dissection, negatively affecting wound healing and delaying adjuvant therapy. Despite numerous surgical and pharmacological approaches, no universally effective strategies have been established. This study aimed to comparatively evaluate the effects of porcine dermal collagen (PDC), tranexamic acid (TXA), and thymoquinone (TQ) on seroma formation and tissue repair. Materials and Methods: A randomized controlled experimental study was conducted using 40 female Wistar albino rats that underwent modified radical mastectomy and axillary dissection. All surgical and postoperative procedures were performed in accordance with the institutional animal welfare and ethical guidelines, including postoperative analgesic administration. The animals were divided into four groups: control, PDC, TXA, and TQ (n = 10 each). Seroma volume was measured on postoperative day 14. Histopathological evaluation, immunohistochemical analysis (FGF2, VEGF, TGF-β1, p53), and quantitative real-time PCR were performed to assess tissue remodeling and molecular responses. Results: All treatment groups demonstrated a significant reduction in seroma volume compared to the control group, with the most pronounced decrease observed in the TQ and TXA groups (p < 0.0001), while PDC showed a moderate effect (p < 0.01). Histopathological analysis revealed increased collagen deposition and fibrin formation in the PDC and TQ groups, whereas TXA exhibited a more limited remodeling profile than the others. Immunohistochemical and molecular analyses showed significant upregulation of VEGF across all groups, with broader and more consistent increases in the PDC and TQ groups. TGF-β1 and FGF2 expression demonstrated region-specific increases, particularly in the thoracic tissue. p53 expression remained relatively stable in the TXA group but was elevated in specific regions in the PDC and TQ groups. Importantly, the increased inflammatory infiltration, edema, vascular proliferation, and fibrin deposition observed in the TQ group may reflect not only active tissue remodeling processes but also prolonged inflammatory activation and enhanced fibrotic responses and should therefore be interpreted cautiously. Conclusions: PDC, TXA, and TQ differentially modulate postoperative seroma formation via distinct biological mechanisms. While TXA primarily exerts a targeted anti-seroma effect and PDC enhances extracellular matrix stabilization, TQ is associated with broader angiogenic, inflammatory, and tissue remodeling responses within this preclinical rat model. These findings should be considered exploratory and hypothesis-generating, and additional mechanistic studies and clinical investigations are necessary before definitive therapeutic conclusions can be established regarding the use of TQ in human breast surgery settings. Full article

After the completion of temporary repair of naval ship equipment, cost settlement has long relied on an ex post auditing model, which results in long cycles and a lack of immediate pricing references for the military. To address this issue, a comprehensive unit price estimation method based on Proximal Policy Optimization (PPO) is proposed, which rapidly generates reasonable unit prices for each process after the repair is completed, thereby providing a quantitative benchmark for negotiation. The unit price estimation problem is formulated as a Markov decision process, and a multi-objective reward function combining range reward, compliance penalty, and final accuracy reward is designed. To alleviate the sparse reward problem, potential-based reward shaping using the Critic network is introduced, which decomposes the final accuracy signal into each pricing step. The clipping mechanism of PPO is adopted to limit the policy update amplitude, thereby improving training stability. Experimental results on 12,000 desensitized real repair records show that the proposed method achieves a mean absolute percentage error (MAPE) of 11.3%, a coefficient of determination (R²) of 0.913, and an abnormal estimation rate (AER) of 3.5%. Compared with standard PPO, the AER is reduced by 59%. The proposed method can sequentially output reasonable unit prices after repair completion, exploring a technical pathway for transforming temporary repair funding from ex post auditing to immediate verification. Full article

Antibiotic-resistant bacteria are widely distributed and threaten public health. Photocatalytic antimicrobial technology can effectively inactivate multidrug-resistant bacteria without readily inducing resistance. We previously showed that oxygen-rich vacancy Bi₂MoO₆ (OBM) exhibits excellent activity against methicillin-resistant Staphylococcus aureus (MRSA), but the underlying molecular mechanisms remain poorly understood. Here, we employed integrated transcriptomics and metabolomics, with qRT-PCR validation, to systematically elucidate the antibacterial mechanism of OBM against MRSA. OBM treatment induced profound transcriptional and metabolic alterations: 231 differentially expressed genes and 206 differentially abundant metabolites were identified. Functional enrichment analysis revealed cooperative involvement in multiple critical pathways, including inhibition of amino acid biosynthesis and protein translation, disruption of cell wall and membrane integrity, induction of oxidative stress, collapse of energy metabolism (suppression of oxidative phosphorylation and impaired ATP synthesis), and imbalance in nucleotide metabolism (down-regulation of DNA helicase and mismatch repair genes, dysregulation of purine/pyrimidine metabolism). These findings demonstrate that OBM photocatalytically inactivates MRSA through a multi-target systemic attack at both the transcriptional and metabolic levels, providing a novel theoretical foundation for the development of photocatalytic materials aimed at controlling MRSA and other drug-resistant bacteria. Full article

Jellyfish stings are the most common type of marine life injuries. However, at present, the treatment measures against jellyfish stings are mostly empirical and supportive, with uncertain therapeutic outcomes, and there is a lack of specific antidotes based on the toxic mechanism of jellyfish venom in clinical practice. In our previous study, polyphenol epigallocatechin-3-gallate (EGCG) was found to neutralize the toxicity of jellyfish Nemopilema nomurai venom (NnV) in vivo and in vitro. Herein we further demonstrated that EGCG exerted its antagonistic effect against NnV through inhibiting the oxidative stress, pro-apoptotic proteins, and systemic inflammatory responses. Subsequently, we constructed a polyethylene glycol (PEG)-EGCG/tetracycline hydrochloride (HTC) co-loaded micellar nanocomplex in order to enhance the stability and bioavailability of EGCG in vivo, which successfully integrated the membrane-repair function of PEG, the enzyme inhibitory effect of HTC and the antioxidant properties of EGCG. Notably, this micellar nanocomplex demonstrated significant protective effects against both functional damage and pathological alterations in a non-lethal NnV-envenomed mouse model. When administered 1 h after NnV envenomation, EGCG (40 mg/kg), HTC and PEG-EGCG (containing 40 mg/kg EGCG) only partially improved abnormal blood biochemical indicators and moderately alleviated histopathologic damage, and PEG-EGCG/HTC containing merely 8 mg/kg EGCG completely mitigated the toxic reactions in envenomed mice. In the preventive regimen, the administration of EGCG, HTC or PEG-EGCG 30 min before exposure showed no significant improvement in abnormal blood biochemical indicators and histopathologic damage, while PEG-EGCG/HTC could still significantly improve the functional impairments and histopathologic damage of the heart and liver in NnV-envenomed mice. These findings suggest the clinical translational potential of PEG-EGCG/HTC against jellyfish envenomation. Full article

Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), advanced pT stage (p = 0.0003) and L1 status (p = 0.0019) in testicular seminoma, high grade (p < 0.05), advanced pT (p < 0.0001), and high UICC stage (p = 0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p = 0.0396), and nodal metastases in papillary thyroid cancer (p = 0.0332). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by a complex etiology and a protracted disease course. Active ingredients from traditional Chinese medicine (TCM), by leveraging the holistic regulatory advantages of anti-inflammatory activity, immune barrier preservation, and gut microbiota regulation, have shown unique therapeutic potential in the intervention of UC. Although bottlenecks such as unclear targets, fragmented mechanisms of action, and poor druggability constrain the clinical translation of TCM active ingredients, current research efforts are dedicated to overcoming these obstacles. This article reviews the latest research progress (2021–2026) on TCM active ingredients for UC treatment. It analyzes the anti-UC mechanisms from three core dimensions: chemical diversity and pharmacodynamic characteristics, validation of direct targets, and indirect regulation through the “gut microbiota–metabolite” axis. Moreover, it emphasizes recent breakthroughs in druggability optimization technologies, including carrier-based nano drug delivery systems (NDDS), carrier-free NDDS, co-delivery NDDS, and prodrug design strategy. Research demonstrates that TCM active ingredients achieve therapeutic effects by modulating inflammatory signaling networks, restoring intestinal immune homeostasis, repairing the mucosal barrier, and remodeling the gut microenvironment. Simultaneously, the application of novel delivery strategies effectively resolves issues such as poor solubility, low oral bioavailability, and insufficient colon targeting. Finally, this review suggests that future research on TCM active ingredients for UC therapy should concentrate on systematically clarifying multi-level mechanisms and designing clinically translatable smart drug delivery strategies, aiming to provide a theoretical basis and practical reference for promoting TCM modernization and innovative UC drug development. Full article