Search Results (49,982)

Oxidative stress in intestinal epithelial cells has been increasingly recognized as a key factor in various intestinal disorders. Gastrodia elata polysaccharide-2 (GEP-2), a water-soluble polysaccharide known for its antioxidant properties, has shown potential against intestinal injury. However, its effects on intestinal epithelial cells and the molecular mechanisms involved are not yet fully understood. In this study, we established a hydrogen peroxide (H₂O₂)-induced oxidative stress model using human colonic epithelial cells (NCM460) to evaluate the protective effects of GEP-2. We assessed cell viability, antioxidant enzyme activities, reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP). The results demonstrated that GEP-2 pretreatment significantly improved the viability of NCM460 cells subjected to H₂O₂ damage. Additionally, it could enhance the antioxidant defense, reduce the levels of ROS, malondialdehyde (MDA), and maintain the MMP. Transcriptomic analysis identified 169 differentially expressed genes upregulated in the glutathione metabolism. JAK-STAT pathway and downregulated in inflammation. Furthermore, it was shown that GEP-2 treatment activated the Nuclear factor erythroid 2-related factor 2 (Nrf2)/quinone oxidoreductase 1 (NQO1)-mediated antioxidant response and promoted the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Therefore, GEP-2 exerts multi-targeted cell protection by coordinating the Nrf2/NQO1 antioxidant axis and the JAK/STAT survival signaling pathway, providing a theoretical basis for the development of novel antioxidants. Full article

Unmanned aerial vehicles (UAVs) acting as mobile aerial edge platforms can deliver on-demand communication and computing for the Internet of Vehicles (IoV) via flexible deployment and line-of-sight (LoS) links, improving reliability and reducing latency. However, high vehicle mobility, time-varying channels, and limited onboard energy make task offloading and resource coordination challenging. This paper studies joint task offloading and resource allocation in a UAV-assisted IoV system, where the UAV selects its hovering position from discrete candidate sites each time slot and splits vehicular tasks between the UAV and a roadside unit (RSU) to relieve backhaul congestion and enhance edge resource utilization. Considering vehicle mobility, multi-stage queue dynamics, and UAV energy consumption for communication, computation, and movement, the online optimization of position selection, task splitting, and bandwidth allocation is formulated as a constrained Markov decision process (CMDP). The goal is to maximize the number of tasks completed within the latency deadlines while satisfying the UAV energy budget. To solve this CMDP, we propose a graph-attention-based constrained twin delayed deep deterministic policy gradient (GAT-CTD3) algorithm. A graph attention network captures spatial correlations and resource competition among active vehicles, while a Lagrangian TD3 framework enforces long-term energy constraints and improves learning stability via twin critics, delayed policy updates, and target smoothing. The simulation results demonstrate that it outperforms the comparative scheme in terms of task completion rate, delay, and energy consumption per completed task, and exhibits strong robustness in situations with dense traffic. Full article

Satellite glial cells (SGCs) are morphologically unique peripheral glial cells that surround neuronal somas in sensory, sympathetic, and parasympathetic ganglia. Satellite glial cells communicate with neurons that they ensheathe and form a distinct structural and functional unit. Following peripheral nerve injury, satellite glial cells undergo remarkable morphological changes, including gliosis, and help regulate the microenvironment surrounding neuronal somas. The expression of many satellite glial cell markers such as glial fibrillary acidic protein (GFAP) and connexin-43, pro-inflammatory cytokines, and growth factors in satellite glial cells is altered in these cells. Injury responses of satellite glial cells, particularly the activation of peroxisome proliferator-activated receptor α (PPARα), contribute to enhanced axonal regeneration. Targeting satellite glial cells may therefore offer novel therapeutic strategies for the treatment of peripheral nerve injury. Full article

Prostate cancer (PCa) progression is critically driven by androgen receptor (AR) signaling, which integrates hormonal cues with metabolic programs supporting tumor growth, survival, and therapy resistance. Emerging evidence suggests that intermittent fasting (IF) and related dietary interventions—such as time-restricted eating (TRE), alternate-day fasting (ADF), and fasting-mimicking diet (FMD)—modulate systemic metabolism, including reductions in insulin and insulin-like growth factor 1 (IGF-1), and induce intracellular nutrient stress that can influence AR activity, splice variant expression (e.g., AR-V7), and downstream metabolic pathways. This systematic literature review (Scopus, PubMed, Web of Science; publications up to December 2025; search terms: “prostate cancer,” “androgen receptor,” “AR splice variants,” “intermittent fasting,” “fasting mimicking diet”, “metabolism,” “therapy resistance”) summarizes preclinical and clinical studies addressing the impact of IF on AR signaling, lipogenesis, mitochondrial function, redox homeostasis, and therapy response. Preclinical studies indicate that IF can reduce AR expression, impair nuclear translocation, modulate AR splice variants such as AR-V7 via nutrient-sensitive splicing mechanisms, and enhance sensitivity to androgen deprivation therapy and AR-targeted agents. Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC. Full article

The adhesion G protein-coupled receptor F5 (ADGRF5) has been implicated in modulating immune responses in cancer; however, its role in inflammatory bowel diseases (IBDs), particularly colitis, remains largely unexplored. In this study, we aimed to design and characterize novel peptide agonists derived from the ADGRF5 Stachel sequence, as well as to evaluate their therapeutic potential in preclinical colitis models. In silico analysis and single amino acid substitutions within the ADGRF5 tethered agonist sequence, combined with functional assays in ADGRF5-overexpressing cells, including calcium mobilization and inositol phosphate production, were employed to assess the activity of novel ADGRF5 agonists. Western blot technique and murine model of colitis were used to evaluate downstream signaling pathways and immunomodulatory effects of ADGRF5 ligands. We identified a series of peptides exhibiting significantly enhanced ADGRF5 agonist activity, achieving up to a 6-fold increase in potency over the wild-type version. We identified critical substitutions within the Stachel sequence, namely S11N and D13S, as essential for improving agonistic activity. Finally, using these novel ADGRF5 agonists, we demonstrated their potent anti-inflammatory effects in vivo, showing that ADGRF5 activation ameliorates experimental colitis, as evidenced by reduced macroscopic damage scores and improved colon architecture. These findings establish ADGRF5 as a potential therapeutic target for colitis and highlight the promise of Stachel-derived peptide agonists for the development of novel anti-inflammatory therapies. Full article

Groundwater used for drinking in settlements located near decommissioned uranium mining facilities may contain elevated naturally occurring radioactive materials, posing long-term public-health concerns. The purpose of this study was to evaluate the radiological quality of groundwater used for drinking in the Saumalkol settlement by applying gross alpha–beta screening and isotope-specific analysis of ²²⁶Ra and ²²⁸Ra to identify the main contributors to groundwater radioactivity and estimate the associated radiation dose from water consumption. Groundwater samples were analyzed using gross alpha–beta screening and isotope-specific determination of ²²⁶Ra and ²²⁸Ra by radiochemical separation and low-background counting, and ingestion doses were estimated using international dose coefficients. Gross alpha activity averaged 2.26 ± 0.96 Bq/L, with most samples exceeding the WHO screening value of 0.5 Bq/L, while gross beta activity averaged 0.65 ± 0.17 Bq/L. Mean activity concentrations of ²²⁶Ra and ²²⁸Ra were 0.17 ± 0.03 Bq/L and 1.47 ± 0.9 Bq/L, respectively, with significantly higher ²²⁸Ra in deep boreholes and a systematic predominance of ²²⁸Ra over ²²⁶Ra (p < 0.05), indicating a thorium-controlled geochemical signature in fractured crystalline aquifers. The estimated annual committed effective ingestion dose from radium isotopes was 0.46 mSv, exceeding the reference level of 0.1 mSv for drinking-water exposure. These findings demonstrate that groundwater radioactivity in Saumalkol is dominated by radium from the thorium series and highlight the need for sustained radionuclide-specific monitoring and targeted water management strategies in uranium-affected regions. Full article

Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads to loss of p53 function. This review systematically elucidates the molecular mechanisms of this pathway and summarizes diverse targeted therapeutic strategies, including small-molecule MDM2 inhibitors, mutant p53 reactivators, and innovative modalities such as gene therapy and Proteolysis Targeting Chimeras (PROTACs). Despite demonstrating potent preclinical activity with low IC₅₀ values, the clinical translation of these agents has faced significant challenges. Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity. Full article

Background: Shenqi granule (SQG) was used clinically to strengthen the spleen and boost energy, alleviating physical weakness and limb fatigue caused by energy deficiency. However, the specific effects and potential molecular mechanisms of SQG in myocardial infarction (MI) treatment remain to be clarified. Methods: This study thoroughly evaluates SQG’s role in improving MIRI in rats using a biological approach. Network pharmacology, weighted gene co-expression network analysis (WGCNA), receiver operating characteristic (ROC), and immune landscape analysis were used to analyze components and key molecular targets. The therapeutic targets of SQG were then validated through molecular docking, molecular dynamics simulation, and experiments. Results: SQG reduced myocardial infarct size and improved myocardial function in rats. Network pharmacology analysis found that six bioactive compounds in SQG could target four proteins. Using WGCNA and ROC, two key targets of SQG were identified, MMP9 and ADH1C. Importantly, integrating PPI network prediction, molecular docking, and expression correlation analyses, MMP9 and ADH1C demonstrate strong physical binding potential and expression association, suggesting their possible involvement in MIRI-related pathways through the immune microenvironment. Molecular experiments and other methods confirmed that the five active ingredients in SQG (luteolin, quercetin, hederagenin, 7-O-methylisomucronulatol, and stigmasterol) can exert cardioprotective effects by stably binding to MMP9/ADH1C. Conclusions: SQG reduces myocardial infarct volume and enhances myocardial function in MIRI rats, likely via inhibiting MMP9 and ADH1C expression. This suggests SQG’s potential as a therapeutic agent for MI, with findings offering strong scientific support for SQG’s use in cardiovascular disease research. Full article

Background/Objectives: Diet quality and physical activity are modifiable lifestyle factors linked to depressive symptoms, but their joint association—and potential variation by sex and age—remains unclear, particularly in Asian populations. This study examined the joint association of diet quality, measured by the Korean Healthy Eating Index (KHEI), and physical activity (PA) with depressive symptoms in Korean adults. Methods: We analyzed 17,737 adults aged ≥20 years from 2014, 2016, 2018, and 2020 KNHANES. Diet quality and PA were each dichotomized at the median to construct four lifestyle groups. Depressive symptoms were defined as Patient Health Questionnaire-9 (PHQ-9) ≥ 10. Survey-weighted multivariable logistic regression adjusted for sociodemographic factors, health-related behaviors, and major chronic diseases was performed, and stratified analyses were conducted by sex and age to explore potential variation across subgroups. Results: Overall, 4.6% of participants had depressive symptoms. Compared with the Low KHEI & Low PA group, the High KHEI & High PA group had substantially lower odds of depressive symptoms (aOR 0.55, 95% CI 0.42–0.73). In sex-stratified analyses, this joint association was significant only among women (aOR 0.48, 95% CI 0.35–0.66). In age-stratified analyses, significant associations were observed in adults aged 45–65 years (aOR 0.42, 95% CI 0.26–0.66) and ≥65 years (aOR 0.41, 95% CI 0.27–0.63). Conclusions: High diet quality combined with high physical activity was associated with markedly lower odds of depressive symptoms, particularly among women and middle-aged to older adults. These findings support integrated lifestyle strategies targeting both diet quality and physical activity, tailored to demographic and social contexts to enhance mental-health benefits across diverse populations. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and remains a leading cause of cancer-related mortality worldwide. EGFR-targeted tyrosine kinase inhibitors (TKIs) have substantially improved outcomes in EGFR-mutant NSCLC; however, primary and acquired resistance continues to limit their long-term efficacy. HER3 (receptor tyrosine-protein kinase ErbB3), a member of the ErbB receptor family, has been implicated in TKI resistance through heterodimerization with EGFR and HER2, leading to downstream PI3K/AKT pathway activation. Despite its biological plausibility as a resistance mediator, the clinical significance of HER3 expression as a prognostic and predictive biomarker in EGFR-mutant NSCLC has not been thoroughly characterized in real-world cohorts. Materials and Methods: This retrospective, single-center study included 52 patients diagnosed with EGFR-mutant NSCLC who received TKI therapy at Afyonkarahisar Health Sciences University between January 2011 and September 2023. HER3 protein expression was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumor tissue sections using the Huabio anti-HER3 antibody (clone PD00-44, 1:2000 dilution). Staining in more than 30% of tumor cells was considered HER3-positive; membranous staining intensity was scored on a 1–3 scale. Progression-free survival (PFS1, PFS2) and overall survival (OS) were analyzed using the Kaplan–Meier method and log-rank test. Statistical significance was set at p < 0.05. Results: Of 52 patients (55.8% female; mean age 64.5 years), 59.6% received chemotherapy and 40.4% received an EGFR TKI as first-line treatment; erlotinib constituted 71.2% of targeted therapies. In the first-line TKI group, HER3-negative patients had a numerically longer median PFS1 compared with HER3-positive patients (14.0 vs. 7.1 months; p = 0.285); however, this difference did not reach statistical significance and should be interpreted with caution given the small sample size. In contrast, among patients receiving first-line chemotherapy, HER3 staining status did not meaningfully affect PFS1 (4.1 vs. 2.5 months; p = 0.063). In second-line treatment, HER3-positive patients who received TKI after prior chemotherapy demonstrated a PFS2 comparable to or slightly exceeding that of HER3-negative patients (21.8 vs. 19.8 months; p = 0.49), suggesting that the sequencing of chemotherapy before TKI may attenuate the adverse effect of HER3 positivity. Median OS was 15.1 months in HER3-negative patients and 12.7 months in HER3-positive patients (p = 0.824); this numerical difference of approximately 3 months did not reach statistical significance and should therefore be interpreted cautiously. Among patients receiving TKI in the first line, HER3-positive patients had a shorter median OS than HER3-negative patients (9.6 vs. 14.2 months), whereas those receiving TKI in the second line showed a trend toward longer OS in HER3-positive patients (20.5 vs. 17.2 months). Conclusions: HER3 expression was associated with reduced first-line TKI efficacy in EGFR-mutant NSCLC, suggesting a possible role for HER3 in primary TKI resistance; however, these findings are exploratory and did not reach statistical significance. The observation that HER3-positive patients who received chemotherapy before TKI demonstrated outcomes comparable to HER3-negative patients raises the hypothesis that treatment sequencing may potentially influence the impact of HER3 positivity, though this requires prospective validation before any clinical conclusions can be drawn. These results suggest that HER3 expression may warrant further investigation as a candidate biomarker for treatment sequencing decisions and as a potential therapeutic target in EGFR-mutant NSCLC. Prospective studies evaluating chemotherapy–TKI sequencing and HER3-directed agents such as patritumab deruxtecan (HER3-DXd) in HER3-positive patients are needed to confirm these preliminary observations. Full article

The adaptive nature of bacteria and their increasing resistance to conventional therapies demand alternative strategies to effectively control wound infections. At the wound site, dynamic biological processes are easily disrupted by microbial colonization, compromising normal healing. In this study, Zn-based nanoparticles composed of zinc oxide (ZnO) and zinc phosphate (Zn₃(PO₄)₂) were synthesized via a green route using coconut milk and coconut water as biological media. Although ZnO formation via zinc hydroxide intermediates was initially targeted, structural analyses revealed a multiphase Zn-based system resulting from interactions between Zn²⁺ ions and naturally occurring phosphate species in the coconut-derived sources. The resulting material was incorporated into sodium alginate/poly(vinyl alcohol) hydrogel dressings, further enhanced with spirulina and aronia powders. Physicochemical characterization (XRD, SEM, EDS, FTIR), along with swelling and degradation studies, confirmed structural stability and appropriate hydrogel behavior. Antimicrobial testing against Staphylococcus aureus and Escherichia coli demonstrated a dominant antibiofilm effect of the Zn-based nanoparticles, while botanical additives exhibited moderate, time-dependent activity. Biological evaluation demonstrated good cytocompatibility toward human keratinocytes and murine macrophages, with botanical additives mitigating mild nanoparticle-induced cellular responses. Full article

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, emerged as an important contributor to the pathogenesis of diabetes and its complications. Impaired glucose and iron metabolism, and increased oxidative stress, predispose cells—particularly pancreatic β-cells and vascular tissues—to ferroptotic cell death, contributing to β-cell dysfunction, insulin resistance, and the progression of diabetic complications. Hydrogen sulfide (H₂S), an important gasotransmitter, plays a pivotal role in regulating various pathophysiological processes by interfering with key cellular signaling pathways, including those related to cell death. In the context of ferroptosis, H₂S exerts protective effects by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4/glutathione (Nrf2/GPX4/GSH) axis, enhancing cellular antioxidative defenses and inhibiting lipid peroxidation. Furthermore, H₂S modulates key regulators of iron homeostasis and lipid metabolism, including hepcidin, ferritin, and the cystine/glutamate antiporter system (xCT) antiporter, further attenuating ferroptosis. Exogenous administration of H₂S can reverse ferroptosis-induced cellular injury in several pathological settings and improve metabolic outcomes in diabetic models. These findings suggest that targeting H₂S signaling is a promising therapeutic strategy to inhibit ferroptosis and mitigate diabetes-related organ dysfunction. This review summarizes current insights into the molecular interplay between H₂S and diabetes-related signaling pathways, primarily ferroptosis, emphasizing the antiferroptotic therapeutic potential of H₂S-based interventions for the prevention and treatment of diabetic complications. Full article

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca²⁺-activated K⁺ channels type 2.3 (K_Ca 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating K_Ca 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for K_Ca 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and reduced K_Ca 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the K_Ca 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial K_Ca 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction. Full article

Cardoon (Cynara cardunculus var. altilis DC.) is a Mediterranean crop valued for biomass production and bioactive compounds; however, information on the use of biostimulants in soilless systems remains limited. This study evaluated the effects of two biostimulants, a legume-derived protein hydrolysate (PH) and an Ascophyllum nodosum seaweed extract (SW), applied as weekly foliar sprays, on growth, physiological performance, mineral composition, and phytochemical traits of cardoon cultivated in a floating system. Biostimulant application significantly affected plant performance, inducing distinct treatment-dependent responses. Both PH and SW increased fresh and dry biomass compared with untreated plants. SW predominantly promoted vegetative growth, chlorophyll content, and nutrient accumulation, whereas PH markedly enhanced nutraceutical quality by increasing total phenolic content and antioxidant activity, reaching 64.4 mg GAE g⁻¹ dry extract and the lowest IC₅₀ value (172 µg mL⁻¹). Harvest timing modulated the magnitude of biostimulant effects, with maximum biomass yield observed at intermediate developmental stages (up to 8.17 kg m⁻²), while phenolic concentration and antioxidant capacity declined at later stages. Multivariate analyses confirmed that PH and SW induced complementary metabolic strategies. Overall, the biostimulant type emerged as the primary driver of plant response, with harvest timing acting as a modulating factor. Targeted biostimulant management, therefore, represents a promising strategy for optimizing the productivity and phytochemical quality of cardoon in soilless cultivation systems. Full article