Search Results (4,417)

Background/Objectives: Recurrent oral ulceration (ROU) is the most prevalent disorder of the oral mucosa, affecting approximately 20% of the global population. Current therapies are limited by adverse effects and high recurrence rates. Ai-Fen, enriched in the anti-inflammatory monoterpenoid L-borneol (54.3% w/w), exhibits therapeutic potential but suffers from poor aqueous solubility and low bioavailability. This study aimed to improve the physicochemical properties and in vivo efficacy of Ai-Fen through the preparation of solid dispersions. Methods: Ai-Fen solid dispersions (AF-SD) were prepared by a melt-fusion method using polyethylene glycol 6000 (PEG 6000) as the carrier. An L₉(3³) orthogonal design was employed to optimize three critical parameters: drug-to-carrier ratio, melting temperature, and melting duration. The resulting dispersions were systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). A chemically induced ROU model in rats (n = 8 per group) was established to evaluate the effects of AF-SD on ulcer area, serum inflammatory cytokines (TNF-α, IL-6), vascular endothelial growth factor (VEGF) levels, and histopathological outcomes. Results: The optimal formulation was obtained at a drug-to-carrier ratio of 1:2, a melting temperature of 70 °C, and a melting time of 5 min. Under these conditions, L-borneol release increased 2.5-fold. DSC and PXRD confirmed complete conversion of Ai-Fen to an amorphous state, while FTIR revealed a 13 cm⁻¹ red shift in the O-H stretching band, indicating hydrogen-bond formation. In vivo, AF-SD reduced ulcer area by 60.7% (p < 0.001) and achieved a healing rate of 74.16%. Serum TNF-α and IL-6 decreased by 55.5% and 49.6%, respectively (both p < 0.001), whereas VEGF increased by 89.6% (p < 0.001). Histological analysis confirmed marked reduction in inflammatory infiltration, accelerated re-epithelialization (score 2.50), and a 5.9-fold increase in neovascularization. Conclusions: AF-SD markedly enhanced the bioavailability of Ai-Fen through amorphization and accelerated ROU healing, likely via dual mechanisms involving suppression of nuclear factor kappa-B (NF-κB)-mediated inflammation and promotion of angiogenesis. This formulation strategy provides a promising approach for modernizing traditional herbal medicines. Full article

Background: Pediatric craniofacial fractures represent a distinct clinical entity characterized by unique anatomical and developmental factors that differentiate them from adult facial trauma. Despite their relative rarity, these injuries pose diagnostic and therapeutic challenges due to the presence of active growth centers and the potential for long-term functional and esthetic sequelae. Methods: A retrospective observational study was conducted among pediatric patients aged 0–17 years treated for craniofacial fractures between 2020 and 2024 at the Department of Cranio-Maxillofacial Surgery, University Hospital in Kraków, Poland. Demographic data, injury mechanisms, fracture distribution, treatment modality, and associated injuries were analyzed. Multivariate logistic regression was applied to identify predictors of surgical intervention. Results: Ninety-eight patients met the inclusion criteria. The mean age was 12 years, with a male predominance. Midfacial fractures were most common, with orbital floor fractures representing the single most frequent injury. Surgical management was performed in 72 cases, predominantly using the transconjunctival approach and autologous bone grafting. Orbital floor fractures were identified as the only independent predictor of operative treatment (p < 0.05). Central nervous system trauma was the most frequent concomitant injury. No significant changes in etiology or fracture distribution were observed during the COVID-19 pandemic. Conclusions: Pediatric craniofacial trauma follows a reproducible, age- and mechanism-dependent pattern. Effective management requires individualized, growth-preserving, and function-oriented treatment strategies. Standardization of care protocols and multicenter prospective studies are essential to optimize outcomes and develop evidence-based, age-specific guidelines for the management and prevention of pediatric facial fractures. Full article

The onset of puberty is a critical developmental milestone regulated by complex neuroendocrine networks that integrate genetic, metabolic, and environmental cues. Among the molecular systems coordinating this transition, neurotrophins—including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, and neurotrophin-4/5—have emerged as important modulators of hypothalamic maturation and the activation of gonadotropin-releasing hormone (GnRH) neurons. Beyond their established roles in neuronal survival and differentiation, neurotrophins contribute to hypothalamic circuit plasticity, influence GnRH neuronal activity, and participate in the integration of metabolic and environmental signals relevant to reproductive maturation. Experimental studies, primarily based on animal and cellular models, demonstrate that BDNF and its receptor play a role in normal pubertal onset, whereas disruptions in neurotrophin signaling have been implicated in central precocious puberty, delayed puberty, and hypogonadotropic hypogonadism. In humans, available evidence is more limited and derives mainly from genetic studies, circulating neurotrophin measurements, and clinical observations. This review provides an integrative synthesis of current experimental and clinical data on neurotrophin-mediated regulation of pubertal timing, highlighting both physiological mechanisms and pathological conditions. While neurotrophins represent promising modulators at the intersection of neurodevelopment, metabolism, and reproduction, further longitudinal and translational human studies are required to define their diagnostic and therapeutic potential in pediatric endocrinology. Full article

Nonylphenol (NP) bioremediation is constrained by the scarcity of efficient and non-pathogenic degrading strains. To clarify the role of acetyl-CoA C-acetyltransferase (AtoB) in NP degradation, we generated an atoB-overexpressed strain (LY-OE) from the environmentally tolerant Bacillus cereus LY and compared its degradation rate with the wild type using HPLC. Untargeted lipidomics was conducted to characterize metabolic responses under NP stress, and key differential lipid metabolites (DELMs) were further validated by ELISA. Additionally, AtoB concentration and ATP content were quantified using commercial assay kits in Bacillus cereus. LY-OE showed a markedly higher NP degradation rate (96%) than LY (85%). Lipidomic analysis identified 34 significant DELMs (VIP > 1, p < 0.05), including elevated cardiolipin (CL) and phosphatidylglycerol (PG), and reduced phosphatidylcholine (PC) and triglycerides (TG). ELISA confirmed these changes (p < 0.01 or p < 0.001), consistent with lipidomic findings. LY-OE showed significantly higher AtoB concentration during the logarithmic growth phase and exhibited higher ATP content during NP degradation. These findings suggest that atoB overexpression enhances NP degradation by both boosting energy supply and remodeling lipid metabolism. This work identifies atoB as a key factor for NP biodegradation and provides a promising strategy for developing high-performance bioremediation strains. Full article

Background/Objectives: Knee osteoarthritis (KOA) is a multifactorial and degenerative disease. Growth differentiation factor 5 (GDF5) polymorphism rs143384 G > A is associated with reduced gene expression and musculoskeletal pathologies. This study aimed to evaluate the association between this functional polymorphism and clinical variability and disease severity among patients with KOA in an admixed population. Methods: This cross-sectional observational study enrolled 224 Brazilian patients with KOA, who were evaluated and classified according to disease severity. Results: The median age was 64 (44–84) years; 75.9% of the patients were female, 50.9% were shorter than 1.60 m, and 67.4% were obese or morbidly obese. The disease severity distribution was 64.7% grades I–III and 35.3% IV–V. Patients with KOA who were over 70 years had significantly more advanced grades (OR = 9.3; 95% CI = 3.4–26), in either female group (OR = 8.2; 95% CI = 2.6–26). The minor allele frequency of the GDF5 rs143384 A variant was 41.7% in the overall KOA case group, increasing with disease severity (39.7% in grades I–III versus 45.6% in IV–V). After adjusting for the confounding factors (age and BMI) the GDF5 GA + AA genotype was significantly associated with higher KOA severity IV–V in female patients (OR = 2.5; 95% CI = 1.2–5.3). Additionally, the mean height of female KOA patients with the GDF5 GA + AA genotype (1.56 ± 0.07 m) was significantly shorter than that of patients with the GG genotype (1.59 ± 0.08 m). Conclusions: The GDF5 rs143384 polymorphism was associated with greater KOA severity and shorter stature in female patients. These results suggest that this variant may contribute to phenotypic variability in patients with knee osteoarthritis, helping to refine clinical characterization and stratification in this population, contributing to personalized diagnoses and guiding future changes in treatment guidelines for knee osteoarthritis. Full article

Balancing tourism industry (TI) growth and ecological protection is critical for sustainable development in the Yellow River Basin (YRB), China’s vital ecological security barrier and economic belt. However, existing research lacks a spatial perspective on the coordinated development between TI and inclusive green growth (IGG), with limited understanding of cross-regional spillover mechanisms. Based on panel data from 75 cities in the YRB (2011–2023), this study constructs a comprehensive evaluation system encompassing the scale, structure, and potential dimensions of the TI and the economic, social, livelihood, and environmental dimensions of IGG. The study employs the coupling coordination degree (CCD) model, exploratory spatial data analysis (ESDA), and the Spatial Durbin Model (SDM) to examine spatiotemporal evolution and spillover effects. The results reveal an upward yet fluctuating coordination trend with pronounced spatial heterogeneity, characterized by a “downstream–midstream–upstream” gradient pattern, dual-core radiation centered on the Jinan–Qingdao and Xi’an–Zhengzhou agglomerations, and persistent High–High clusters in the Shandong Peninsula contrasted with Low–Low clusters in the upstream Qinghai–Gansu–Ningxia region. Critically, new-quality productive forces exert significant positive direct and spillover effects, while industrial structure and government intervention have inhibitory spatial effects on adjacent cities. Regional heterogeneity analysis confirms factor-endowment-driven differentiation across upstream, midstream, and downstream areas. These findings advance spatial spillover theory in river basin contexts and provide evidence-based pathways for balancing economic growth with ecological protection in ecologically sensitive regions worldwide, directly supporting multiple UN Sustainable Development Goals. Full article

The shipping service industry plays a pivotal role in enhancing port competitiveness and fostering urban economic growth, yet limited studies systematically integrate its spatial temporal dynamics with the processes driving port–city synergy. This study constructs a three-dimensional analytical framework encompassing port operations, urban economic development, and shipping service industry agglomeration. Using data from 13 port cities in Jiangsu Province (2015–2023), we apply the entropy weight method, coupling coordination degree model, relative development model, and panel Tobit regression to evaluate interaction intensity, coordination patterns, and influencing factors. Results reveal a clear spatial gradient in coupling coordination, higher in southern Jiangsu and lower in the north, driven by disparities in economic foundations, port capacities, and service industry structures. In most cities, port operations and urban economies lag behind shipping service industry agglomeration, reflecting the predominance of low- and mid-end services. Port construction level, cargo and container throughput, economic development, openness, fixed asset investment, and population density significantly promote coordination, whereas R&D capacity shows no significant effect. The findings advance understanding of port–city service interlinkages and provide targeted policy recommendations for differentiated regional development, infrastructure enhancement, and upgrading toward high-end shipping services, with implications for maritime regions worldwide. Full article

Cold stress limits cucumber productivity, and grafting onto tolerant rootstocks offers a promising strategy for improving resilience. This study compared the responses of cucumber heterografts and self-grafts exposed to different cold temperatures, aiming to uncover the molecular basis of grafting-mediated tolerance. Morphological observations showed that grafting onto Cucurbita ficifolia and C. maxima X C. moschata cv. Tetsukabuto rootstocks improved plant growth under moderate cold, while extreme stress remained lethal. Transcriptome analysis revealed that heterografts displayed broader and more sustained differentially expressed genes than self-grafts. Gene ontology (GO) enrichment in heterografts indicated early activation of structural, regulatory, and metabolic processes, with continued enrichment at later stages. KEGG analysis highlighted plant hormone signaling as a central pathway modulated by heterografting, with selective regulation of auxin, ethylene, and ABA signaling. Heterografts activated key regulators, including MAPK3-like, TIFY5A, and CPK28, which were strongly expressed, alongside transcription factors from NAC, CAMTA, WRKY, and MYB families, suggesting coordinated regulation of cold-responsive networks. These results demonstrate that heterografting enhances cold tolerance by orchestrating multi-layered molecular responses, including hormone modulation, stress signaling, and transcriptional factors. This underscores the potential of grafting onto cold-tolerant rootstocks as a practical strategy for cucumber cultivation in cold-prone environments. Full article

Background/Objectives. Prostate cancer (PCa) is among the leading causes of death from cancer in men. Frequent use of androgen receptor inhibitors induces PCa transdifferentiation, leading to poorly differentiated neuroendocrine PCa (NEPC). ROR2 is critical for NEPC pathogenesis by activating ASCL1, promoting lineage plasticity. Protein lysine methylation mediated by N-lysine methyltransferases SMYD2 and its downstream effector EZH2 upregulates the NEPC marker ASCL1 and enhances c-MET signaling, promoting PCa aggression. Epidemiological studies suggest a lower incidence of certain malignancies in Mediterranean populations due to their intake of an olive-phenolics-rich diet. Methods. Cell viability, gene knockdown, and immunoblotting were used for in vitro analyses. A nude mouse NEPC xenograft model evaluated the anti-tumor efficacy of purified and crude oleocanthal. Xenograft tumors were subjected to RNA-seq, qPCR, and Western blot analyses, with clinical validation performed using tissue microarrays. Results. A tissue microarray analysis showed that SMYD2 expression was significantly elevated in PCa tissues with higher IHS versus normal prostate tissue cores. The olive phenolic S–(–)–oleocanthal (OC) suppressed the de novo NEPC NCI-H660 cells proliferation. Male athymic nude mice xenografted with the NCI-H660-Luc cells were used to assess OC effects on de novo NEPC progression and recurrence. Male NSG mice transplanted with LuCaP 93 PDX tumor tissues generated a heterogeneous in vivo model used to assess OC effects against t-NEPC progression. Daily oral 10 mg/kg OC administration significantly suppressed the NCI-H660-Luc tumor progression and locoregional recurrence after primary tumor surgical excision. OC treatments effectively suppressed the progression of LuCaP 93 PDX tumors. OC-treated tumors revealed downregulation of ROR2, ASCL1, SMYD2, and EZH2, as well as activated c-MET levels versus the placebo control. RNA sequencing of the collected treated NEPC tumors showed that OC disrupted NEPC splicing, translation, growth factor signaling, and neuronal differentiation. Conclusions. This study’s findings validate OC as a novel lead entity for NEPC management by targeting the ROR2-ASCL1-SMYD2-EZH2-c-MET axis. Full article

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin–NFAT or oxygen-binding globins—offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell–derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation. Full article

Hepatoblastoma (HB), the most common pediatric liver malignancy, tends to be highly curable although advanced or recurrent disease has less favorable outcomes. Because patients are invariably <3–4 years of age, chemotherapies can cause significant long-term morbidities. Immortalized HB cell lines could be of great utility for drug screening, for the identification of novel therapeutic susceptibilities, and for studies requiring highly regulated and/or rapidly changing in vitro environments. However, HB research is hampered by a paucity of these lines that could be used for such purposes, with only two human cell lines being readily available, neither of which represents the most common HB molecular subtypes. Recently, immortalized cell lines have been derived from murine HBs that are driven by the most common oncogenes and tumor suppressors associated with human tumors. These comprise five distinct groups associated with the deregulation of each of the four possible combinations of oncogenic forms of the β-catenin, YAP and NRF2 transcription factors or the over-expression of MYC. All five groups share many of the attributes and molecular signatures of actual human HBs. In addition, they have been used for purposes as diverse as identifying novel molecular targets through the use of Crispr-based screens and the demonstration that some HB cells can trans-differentiate into endothelial cells that facilitate tumor growth. The experience gained from these models and advances in the propagation of human hepatocytes in mice suggests that it may soon be possible to generate bespoke human immortalized human cell lines. Full article

Understanding evapotranspiration (ET) dynamics under community composition transitions in grasslands is crucial for interpreting alpine ecosystem responses to climate change. We investigated variations in ET and its components during the growing season across five alpine grassland transition types in the Source Region of the Yellow River (SRYR) from 1986 to 2018, integrating climatic, vegetation, and soil factors. Under warming and wetting conditions, ET increased significantly by 1.17 mm yr⁻¹, accounting for 79.39% of annual precipitation, while soil moisture declined slightly. A pronounced temperature–precipitation decoupling emerged between alpine meadow-origin (AM-origin) and alpine steppe-origin (AS-origin) transitions, indicating differential hydrological responses driven by community composition. Vegetation growth increased across all transitions, yet its regulation of ET components varied by transition type. Transpiration dominated ET increases, contributing over 80% in AM-origin and 100% in AS-origin transitions. Soil evaporation exhibited contrasting trends: decreasing in AS-origin transitions due to enhanced soil insulation from vegetation growth, but increasing in AM-origin transitions, thereby reducing soil moisture. Interannual ET growth rates and seasonal fluctuations were greater in AM-origin than in AS-origin transitions. A critical turning point in ET trends, caused by changes in precipitation, revealed the divergent hydrological trajectories among the transitions. In AM-origin transitions, temperature primarily drove ET increases, causing soil drying (strongest in AM to TS), whereas in AS-origin transitions, precipitation dominated, resulting in soil wetting (more pronounced in AS to AM). These findings demonstrate that the directionality of compositional transitions governs hydrological responses more strongly than absolute vegetation states. Full article

Optimizing resource allocation is crucial for enhancing Total Factor Productivity (TFP). This study investigates the impact of differentiated industrial land supply (DILS) on industrial Total Factor Productivity (ITFP), a topic essential for optimizing territorial spatial layouts and promoting high-quality industrial development. Using panel data from 282 Chinese cities (2007–2021) and a Spatial Durbin Model (SDM), we analyze the spatiotemporal effects of this factor. The results indicate a weakening trend in DILS over time, with a spatial pattern of lower intensity in the east and higher intensity in the west, while ITFP shows an upward trend, with higher levels in the east. Nationally, increased DILS impedes ITFP growth, a finding with robust implications for alternative approaches. This impact demonstrates significant spatiotemporal heterogeneity: at the macro-scale, eastern China shows an inverted U-shape, while the central and western regions exhibit negative impacts. At the meso-scale, the Yangtze River Economic Belt shows negative effects, while the Yellow River Basin displays an inverted U-shape. At the micro-scale, major city clusters show varied relationships (inverted U-shaped, positive, or negative). We conclude that DILS generally hinders ITFP, with effects intensifying and varying significantly across narrowing spatial scales, underscoring the need for region-specific land policies to support high-quality industrial development. This study enriches our theoretical understanding of how resource allocation affects ITFP and provides practical guidance for optimizing industrial land use. Full article

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and often adopt an M2-like immunosuppressive phenotype that promotes tumor growth. Reprogramming TAMs toward an M1-like pro-inflammatory state is an attractive therapeutic strategy. Tumor Treating Fields (TTFields), an FDA-approved, electric-field–based therapy, has recently been suggested to modulate immune responses in addition to its established anti-mitotic activity. Here, we investigated the direct effects of TTFields on macrophage activation and function. Murine bone marrow–derived macrophages (BMDMs) were polarized toward a pro-inflammatory M1-like phenotype or an anti-inflammatory M2-like phenotype and exposed to TTFields. TTFields rapidly activated guanine nucleotide exchange factor-H1 (GEF-H1), and downstream nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1, via c-Jun N-terminal kinase [JNK]) signaling. Functionally, TTFields reprogrammed M2-like macrophages by increasing major histocompatibility complex class II (MHC-II) and cluster of differentiation 80 (CD80); reducing arginase-1 (Arg1); and elevating secretion of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), IL-1β, and IL-12 subunit p70 (IL-12p70). In interferon gamma (IFN-γ)-primed macrophages, TTFields provided a secondary signal, driving myeloid differentiation primary response 88 (MyD88)-dependent expression of inducible nitric oxide synthase (iNOS). In vivo, TTFields reduced tumor burden in an orthotopic murine lung cancer model and increased iNOS expression in both M1-like and a subset of M2-like TAMs. These findings demonstrate that TTFields directly reprogram macrophages toward a pro-inflammatory phenotype, suggesting a novel immunomodulatory mechanism that may enhance anti-tumor immunity in the TME. Full article

Sujiang pigs, a high-quality local Chinese breed, represent a valuable model for investigating muscle development and improving meat production through genetic selection. Skeletal muscle satellite cells (MuSCs) are essential regulators of muscle growth, with differentiation tightly controlled by specific genes and signaling pathways. In this study, MuSCs were isolated from the gastrocnemius muscle and subjected to mRNA sequencing during proliferation (GM) and differentiation stages (DM1, DM2, and DM4, collectively referred to as DM). A total of 2790 differentially expressed genes (DEGs) were identified, including 1551 upregulated and 1239 downregulated genes. Time-series analysis revealed 16 significant expression patterns. These DEGs were primarily associated with muscle development and differentiation and were enriched in Wnt, PI3K–Akt, JAK–STAT, p53, Hippo, and Apelin signaling pathways. Among them, phosphoribosyl transferase domain containing 1 (PRTFDC1) exhibited pronounced downregulation during differentiation. Functional validation demonstrated that PRTFDC1 overexpression promoted myotube formation and upregulated MYOD1, MYOG, and MYH1 expression, whereas knockdown significantly inhibited differentiation. Furthermore, PRTFDC1 enhanced phosphorylation of key proteins in the cGAS–STING signaling pathway. Collectively, this study elucidates the temporal transcriptional regulation of MuSC differentiation in Sujiang pigs and identifies PRTFDC1 as a novel regulatory factor, providing a molecular foundation for breeding strategies and meat quality improvement. Full article