Search Results (2,469)

Diabetic nephropathy (DN) is a severe diabetic complication with substantial clinical burden. The complex pathogenesis of DN has hindered the development of targeted therapies, creating an urgent need to develop novel strategies that directly address its underlying inflammatory and fibrotic mechanisms. Coreopsis tinctoria (CE) is an edible plant rich in polyphenols, but its mechanism against DN remains understood. An integrated framework combining network pharmacology and machine learning was developed to prioritize active polyphenols and their targets. A multi-layer perceptron classifier, trained on 3.16 million compound–target pairs from Binding DB, predicted interactions between 36 CE polyphenols and 12,030 DN-associated genes. The top 100 targets were subjected to KEGG enrichment analysis, and the identified pathways were validated in a high-fat diet/STZ-induced DN rat model. The MLP model achieved superior performance (AUC-ROC = 0.9219, AP = 0.9592). Five lead polyphenols (flavonoids/chalcones) showed high predicted activity. KEGG analysis revealed enrichment in PI3K-Akt, calcium signaling, metabolic pathways, and cellular senescence. In vivo, CE treatment (150–600 mg/kg/day) dose-dependently improved glucose/lipid metabolism and renal function, and ameliorated histopathological damage, including glomerular hypertrophy, fibrosis, and mesangial expansion. Mechanistically, CE suppressed NFκB/TGFβ/Smad signaling, restored PPARγ and Nrf2/HO-1/FoxO1 antioxidant defenses, and inhibited apoptosis via Bcl-2/Bax regulation. CE exerts multi-target renoprotective effects through coordinated modulation of metabolic, inflammatory, fibrotic, and antioxidant pathways, supporting its potential as a functional food ingredient for DN management. Full article

Natural therapeutic alternatives are increasingly explored in endometriosis, a highly prevalent gynecological disorder with limited therapeutic options. Rosmarinus officinalis (rosemary) has attracted increasing scientific interest due to its biological activity. This study aimed to characterize a hydroethanolic rosemary extract (RE) and evaluate its effects on key cellular processes involved in endometriosis pathophysiology. Major phenolic compounds in RE were quantified by RP-HPLC, and antioxidant activity was assessed using DPPH, ABTS, and FRAP assays. After RE treatment, cell viability (WST-1), migration (wound healing assay), cell cycle distribution (DAPI staining), apoptosis (Annexin V/PI), p21 and cyclin A expression (Western blot), and intracellular ROS levels (DCFH-DA) were evaluated in endometrial stromal (t-HESC, St-T1b) and endometriotic epithelial (12-Z) cells. Phytochemical analysis revealed rosmarinic acid (RA) at 4.2%, while carnosic acid (CA) and carnosol (CS) together accounted for 23.7% of the extract. RE reduced cell viability and cell migration in 12-Z and t-HESC cells (p < 0.05). S-phase accumulation with a concomitant reduction in the G1 phase was observed across all evaluated cell lines (p < 0.05), along with increased p21 and cyclin A expression in stromal cells (p < 0.05). RE induced cell death in both 12-Z (p < 0.05) and St-T1b cells (p < 0.0001). In t-HESC cells, RE reduced both basal and H₂O₂-induced ROS levels (p < 0.01). These findings indicate that RE modulates key mechanisms involved in endometriosis pathophysiology, supporting its multi-target therapeutic potential as a nutraceutical approach for endometriosis management. Full article

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A_2A/A_2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, K_Ca3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated K_Ca3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A_2AAR, A_2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the K_Ca3.1 current in fibroblasts and reduced K_Ca3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A_2AAR or A_2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis. Full article

Burn wound healing is a complex and dynamic process involving coordinated regulation of inflammation, oxidative stress, angiogenesis, and tissue remodeling. Polygonum cuspidatum, a traditional Chinese medicinal herb widely used for trauma- and inflammation-related disorders, represents an important source of bioactive compounds for tissue repair. Piceatannol (PIC), a naturally occurring stilbene constituent of P. cuspidatum, possesses potent anti-inflammatory and antioxidant activities; however, its therapeutic potential in burn wound healing remains insufficiently understood. In the present study, the therapeutic effects and underlying mechanisms of topical PIC were investigated using a murine deep second-degree burn model combined with multiple skin-related cellular models, including keratinocytes, fibroblasts, endothelial cells, and macrophages. PIC markedly accelerated wound closure and improved histological architecture, as evidenced by reduced inflammatory infiltration, enhanced collagen organization, and increased neovascularization. Mechanistically, PIC suppressed NF-κB activation and modulated KEAP1/NRF2-associated redox signaling, thereby alleviating inflammation–oxidative stress crosstalk during wound healing. In keratinocyte–fibroblast co-culture systems, PIC inhibited fibroblast-to-myofibroblast transition, reduced α-smooth muscle actin (α-SMA) expression, and attenuated excessive collagen deposition, suggesting anti-fibrotic activity. In addition, PIC promoted endothelial tube formation through activation of the STAT3–VEGF signaling axis. Collectively, these findings demonstrate that PIC facilitates burn wound repair through coordinated anti-inflammatory, antioxidative, pro-angiogenic, and anti-fibrotic effects. This study provides pharmacological support for the therapeutic potential of P. cuspidatum-derived compounds in burn management and highlights PIC as a promising candidate for topical treatment of burn injuries. Full article

Background/Objectives: Chronic wounds remain a formidable clinical challenge due to the suboptimal efficacy of conventional delivery systems and therapeutics. Textilinin-1, a venom-derived Kunitz-type serine protease inhibitor, has previously established its profile as a potent hemostatic agent. However, its potential as a multifunctional biopharmaceutical for wound management remains largely untapped. This study evaluates the pharmacological effects of Textilinin-1 in preclinical models of cutaneous wound repair. Methods: We employed an integrated platform comprising bioinformatics, in vitro cellular assays, and in vivo murine excisional wounds and a pilot porcine proof-of-concept model to assess the wound healing-promoting effects of Textilinin-1 and explore associated cellular responses associated with key stages of the wound healing cascade. Results: Textilinin-1 was associated with multiple cellular responses relevant to tissue repair. It attenuated M1-like inflammatory activation and showed preliminary growth-inhibitory activity against Staphylococcus aureus under the tested conditions. Concurrently, it enhanced the proliferative and migratory capacity of fibroblasts, endothelial cells, and keratinocytes, which are key cellular targets for wound closure. In pre-clinical pilot porcine and rodent models, Textilinin-1 treatment was associated with accelerated wound contraction and improved structural tissue quality. Conclusions: Our findings provide preclinical evidence that Textilinin-1 may promote cutaneous wound repair and modulate cellular responses relevant to key stages of the wound healing cascade. These results support further investigation of Textilinin-1 as a candidate for wound repair applications. Future studies are required to define its precise molecular mechanisms, evaluate its efficacy in chronic or otherwise compromised wound models, and optimize its topical formulation or hydrogel-based delivery. Full article

Male reproductive health has experienced an unprecedented decline over the past five decades, characterized by substantial reductions in sperm count and testosterone levels. This review provides a comprehensive synthesis of current evidence on the global decline in sperm count and testosterone levels, examining epidemiological trends, underlying mechanisms, environmental drivers, and clinical implications. Sperm concentration declined by 51.6% globally between 1973 and 2018, with an accelerating trajectory post-2000 (from 1.16% to 2.64% per year). Concurrently, multiple independent studies document an age-independent secular decline in testosterone, averaging 1–2% per year across diverse populations. The etiology is multifactorial, involving endocrine-disrupting chemicals (bisphenol A, phthalates, pesticides, dioxins), lifestyle factors (obesity, sedentary behavior, smoking, heat exposure), and disruption of the hypothalamic–pituitary–gonadal axis. At the cellular level, mechanisms include Sertoli and Leydig cell dysfunction, oxidative stress, mitochondrial impairment, and sperm DNA fragmentation. Integrated clinical management combining lifestyle optimization, antioxidant therapy, and targeted endocrine interventions is essential. Prevention through environmental policy and public health initiatives represents the most promising long-term strategy. Full article

Accurate road-event detection and timely alert message dissemination are essential for the safety of connected and automated vehicles. In many scenarios, alert messages must reach not only nearby vehicles but also remote stakeholders, such as traffic management centers, cloud services, and infrastructure operators. This requirement motivates the adoption of cellular-based communication technologies in addition to short-range vehicle-to-everything (V2X) communications for data dissemination. In this work, we investigate vehicle-to-network-to-everything (V2N2X) communications for the dissemination of alert messages generated after the on-board detection of hazardous road events through machine learning (ML) algorithms. Although V2N2X connectivity is well suited for extending data dissemination beyond the local vehicular environment, its capability to guarantee prompt message delivery under strict latency constraints remains an open challenge, particularly when ML inference is integrated into the end-to-end processing pipeline. To address this issue, we develop and experimentally evaluate a proof-of-concept (PoC) platform that combines real-time road-event detection with relevant message dissemination towards both nearby and remote recipients. The proposed framework leverages 5G connectivity and publish/subscribe messaging protocols. The experimental results showcase that dissemination latency is highly influenced by both the adopted type of 5G deployment (private versus commercial networks) and the load conditions at the message broker. Full article

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit. Full article

The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management. Full article

Background: The growing complexity of liquid biopsy in precision oncology demands a structured classification framework that can accommodate its expanding multi-omic scope. As the field has matured from early Tumor Microemboli research—focused on multicellular clusters of circulating tumor cells (CTCs) that drive high-efficiency metastasis—to the broader systemic analysis of the “Tumor Microenvironment” (TME) encompassing malignant and non-malignant components, the need for a hierarchical taxonomy has become evident. Objective: To integrate these diverse data streams into a coherent clinical framework, a multi-tiered classification system is needed. This review proposes a foundational roadmap that formally distinguishes the systemic ecosystem from its physical and functional subsets and highlights their clinical utility in therapeutic decision-making. Proposed Taxonomy: We advocate for the adoption of Circulating Tumor Microenvironment (cTME) as the inclusive term for the systemic environment, encompassing non-cellular factors such as ctDNA, extracellular vesicles, and biophysical attributes. Conversely, physical cellular clusters should be strictly classified as Circulating Tumor Emboli (CTE). Crucially, we define Circulating Tumor-Associated Cells (C-TACs) as the functional cellular subset within the cTME, encompassing single CTCs, CTE, and supporting non-malignant cells like CTECs and CAFs. Clinical Applications: Establishing this distinction allows for the seamless integration of molecular profiling (NGS) and functional assays. We highlight emerging evidence that C-TACs may serve as the primary substrate for Chemo-Response Profiling (CRP), with early proof-of-concept studies reporting high concordance with clinical outcomes that still await independent prospective confirmation. Furthermore, preliminary evidence suggests that identifying these functional units, particularly perioperative CTE, may help predict the efficacy of adjuvant chemotherapy in early-stage malignancies, although this remains to be confirmed in prospective studies. Conclusions: Adopting this unified taxonomy may help advance precision oncology. By recognizing the cTME as the superordinate ecosystem and C-TACs as its functional executors, clinicians may be better positioned to interpret multi-modal liquid biopsy data, providing a conceptual roadmap for integrating these technologies into platforms for personalized cancer management. We emphasize that this framework is intended to be hypothesis-generating and that its clinical applications require prospective validation before routine adoption. Full article

Accurate assessment of vitreous inflammation is essential for the diagnosis, monitoring and management of uveitis. Traditionally, vitritis has been evaluated using subjective clinical grading systems based on vitreous haze and cellular infiltration, which are limited by interobserver variability and poor reproducibility, particularly in cases of mild or subclinical inflammation. In recent years, advances in ocular imaging have enabled the development of more objective, quantitative approaches. Ultra-widefield imaging, optical coherence tomography (OCT) and ultrasound-based techniques have provided new insights into structural alterations within the vitreous. In parallel, automated image analysis and artificial intelligence (AI)-based methods have improved the detection and quantification of inflammatory biomarkers, including vitreous hyperreflective foci and signal intensity-based metrics. Despite these advances, important limitations remain, including a restricted field of view, a lack of standardized segmentation algorithms and an incomplete representation of the entire vitreous cavity. No single modality currently provides a comprehensive and fully reproducible assessment of vitreous inflammation. This review summarizes current qualitative and quantitative methods for evaluating vitreous inflammation, highlighting their respective strengths and limitations. In addition, emerging diagnostic strategies, including multimodal imaging integration, AI-driven analysis and molecular biomarker profiling, are discussed as potential tools to improve accuracy, standardization and clinical applicability. The transition from subjective grading toward objective quantification of inflammatory burden represents a key step in advancing both clinical management and research in ocular inflammatory diseases. Full article

Background: Critical illness leads to profound metabolic, neuroendocrine and immune disorders that affect the prognosis of patients treated in intensive care units (ICUs). The ketogenic diet, a high-fat and low-carbohydrate eating model, is gaining increasing importance as a potential metabolic intervention in the ICU. Preliminary data suggest that the ketogenic diet (KD) may support the control of seizures in a super-refractive epileptic state (SRSE), stabilize glycemia, reduce insulin demand, and modulate the immune response in sepsis. The aim of this review was to present a synthetic presentation of the current state of knowledge regarding use of the KD in intensive care patients. Methods: The review was carried out in accordance with the guidelines of the Joanna Briggs Institute and PRISMA-ScR. PubMed, Scopus, EBSCO, Web of Science, Google Scholar and Cochrane Library databases were searched (10–19 April 2026) using the Population–Concept–Context model. Full-text observational studies, randomized trials and reviews of the use of KDs in ICU patients were included. Data extraction was performed independently by two reviewers. Results: Of the 42 publications identified, seven studies were included in the analysis. The KD was feasible and safe in both critically ill adults and children. In SRSE, most patients achieved stable ketosis within a few days, which often allowed for reduction or discontinuation of anesthetics. In sepsis, the KD led to glycemic stabilization, reduced insulin demand and reduced immune deregulation; in one study, “after day 4, none of the patients in the KD group required insulin treatment.” The KD also showed beneficial effects on cellular bioenergetics and mitochondrial function. The safety profile was acceptable and adverse reactions were manageable with appropriate monitoring. Conclusions: The KD represents a promising, non-pharmacological metabolic intervention in intensive care, particularly in the treatment of SRSE and in the stabilization of glucose metabolism in sepsis and other critical conditions. Despite the growing number of positive clinical observations, the available evidence remains limited due to small samples, heterogeneous protocols, and a lack of randomized trials. Further, well-designed prospective studies are needed to determine optimal KD implementation protocols and identify the patient populations that benefit most. Full article

This study develops an integrated computational framework to assess the passage efficiency of a dam crest serving as a critical inter-regional corridor following a severe explosion event. The framework combines a physics-based damage model with an agent-based cellular automata (CA) approach that incorporates pedestrian behavioral heterogeneity. The damage model conceptualizes three concentric zones: a complete fragmentation zone (0–1.5 m) with total material disintegration, a primary damage zone (1.5–5 m) following an exponential decay in structural integrity, and a secondary damage zone (5–20 m) governed by a power-law attenuation of fragmentation effects. Pedestrian behavior is parameterized by the Allowable Conflict Coefficient (ACC), the inverse of interpersonal friction, and the Emergency Level (EL), which scales the desired velocity. Extensive simulations under stochastic and targeted impact scenarios reveal a consistent evacuation performance hierarchy: Center (C) > Bottom-Left (BL) > Top-Left (TL) > Bottom-Right (BR) ≈ Top-Right (TR). Exit-proximal damage (TR, BR) increased evacuation time by up to 85% compared with central impacts. Results demonstrate a strong coupling between physical friction and urgency: the “faster-is-faster” effect is maximized under low friction (high ACC), while high friction not only suppresses the benefits of elevated EL but can also induce “faster-is-slower” phenomena under extreme conditions. These findings underscore that optimal evacuation strategies depend critically on both impact location and crowd behavior management, providing actionable insights for emergency planning and highlighting the importance of conflict mitigation in enhancing infrastructure resilience. The proposed framework thus offers a versatile and validated simulation tool for emergency planners to proactively assess and optimize evacuation strategies under various damage scenarios. Full article

From the perspective of interactions between energy firm behavior and government intervention strategies, this study develops a contagion control model for energy firm debt default risk utilizing cellular automata and complex network theory. This research investigates the spatio-temporal evolution of risk transmission and evaluates the efficacy of various mitigation protocols through computational simulation. The research results indicate that: (1) An escalation in both the transmission likelihood and the rate of immunity decay significantly amplifies the propagation strength of debt default risks. Conversely, the stability of the energy firm network is bolstered as the probabilities of immunity and recovery increase. (2) The contagion intensity for debt default risk is positively correlated with market noise, the risk appetite of energy firms, and their corporate influence. It is negatively correlated with risk awareness, creditworthiness, regulatory intensity, and policy subsidies. Furthermore, it exhibits an inverted U-shaped relationship with investor sentiment. (3) Within the interconnected network of energy firms, risk contagion can be effectively mitigated not only by enhancing risk perception and credit standing but also by guiding risk preference and managing firm influence. Furthermore, the integration and adjustment of government intervention strategies, such as regulatory intensity and policy subsidies, can more efficiently accelerate the eradication of debt default risk among energy firms. Full article

Background: The formation of wounds or scars often compromises skin anatomy and function, necessitating effective management to restore tissue integrity. Current interventions, including wound debridement, hyperbaric oxygen therapy, antibiotics, wound dressings, and surgical procedures, can be effective but are sometimes limited by high costs and the increasing prevalence of drug resistance. These challenges highlight the need for innovative, cost-effective, and therapeutic alternatives. Method. Our earlier studies assessed the wound closure of wounded human-equivalent epidermal full-thickness skin model (HEFT-SM) with a limited number of Phytoceutical^® retinol micellar formulations for a six-day treatment and found that the retinol micellar formulation accelerated wound closure significantly. In this work, three different types of Phytoceutical^® retinoid formulations, namely 0.3% retinol, 0.3% retinaldehyde, and 0.03% retinoic acid on the early-stage wound healing efficacy and its collagen structure were studied. Haematoxylin and eosin (H&E) staining analysis was used to assess the wound repair of the 3 mm punch wound after two days and the wound healing efficacy defined as the wound diameter contraction in percentage was assessed. The collagen matrix was examined through the use of Masson’s trichrome staining and confocal laser scanning microscopy (CLSM) for both qualitative and spatial assessment. Results. All formulations promoted wound contraction, with efficacy ranging from 15 ± 1% to 35 ± 2% after two days. The 0.3% retinol micelles showed the highest activity (35 ± 2%), followed by retinaldehyde (32 ± 3%) and retinoic acid (15 ± 1%). In addition, all treatments appeared to stimulate collagen architectural changes suggestive of remodelling activity. Conclusions. The enhanced wound healing observed may be attributed to increased cellular proliferation and migration within the wound microenvironment, supporting epidermal differentiation and tissue stratification. Furthermore, this work showed that combination of Masson’s trichrome staining and confocal laser scanning microscopy (CLSM) is a novel approach for qualitative and spatial assessment of collagen structure. Full article