NOS1AP (CAPON) is a signaling adaptor implicated in glioblastoma (GBM) proliferation, but its chemical tractability remains largely unexplored. Here, affinity selection–mass spectrometry screening of 10,000 drug-like compounds identified NGM1, a small molecule scaffold that directly binds NOS1AP. Binding was confirmed by microscale thermophoresis (MST), yielding a dissociation constant of 11.9 ± 7.0 μM. Focused structure–activity analysis and molecular modeling identified structural features associated with NOS1AP recognition and provided a framework for compound optimization. In living cells, NGM1 produced a concentration-dependent reduction in the NanoBRET signal generated by the NOS1AP-NOS1 reporter pair, consistent with perturbation of the complex. NGM1 reduced viability in U87 and U251 GBM cells, with IC50 values of 12.7 ± 0.91 and 17.3 ± 1.04 μM, respectively, while normal human astrocyte viability remained above 50% at 150 μM. Mechanistic studies in U87 cells demonstrated reduced DNA synthesis, G0/G1 cell-cycle accumulation, and induction of apoptosis, accompanied by increased p53 and CDKN1A and decreased CDK6. Collectively, these findings establish the initial chemical tractability of NOS1AP and identify NGM1 as a chemical scaffold for investigating NOS1AP-associated signaling in GBM. The findings also provide a foundation for optimizing NOS1AP-directed compounds.
Ficus carica L., a widely cultivated member of the Moraceae family, is recognized for its rich phytochemical composition and diverse biological activities; however, the influence of harvest season and extraction solvent on its bioactive profile remains insufficiently explored. In this context, leaves collected from Dalaman (Muğla, Türkiye) in April and November were comparatively evaluated in terms of phenolic profiles, antioxidant capacity, enzyme inhibitory potential, molecular docking interactions, and preliminary ADMET properties. Eight extracts were prepared using ethyl acetate, methanol, aqueous ethanol, and water, and phenolic composition was characterized by HPLC-DAD using 42 reference standards. Major contributors to bioactivity included hesperidin, rutin, chlorogenic acid, cynarin, naringenin, and 4-hydroxyresorcinol. Antioxidant activity was assessed via DPPH˙, ABTS˙+, CUPRAC, and β-carotene–linoleic acid assays, while enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and tyrosinase were determined. Hesperidin reached its highest concentration in the water extract FC14 (80.06 mg/g). FC14 showed the strongest DPPH˙ (IC50: 54.46 ± 0.94 μg/mL), ABTS˙+ (IC50: 10.75 ± 0.17 μg/mL), and CUPRAC (A0.5: 95.38 ± 1.69 μg/mL) activities, whereas the ethyl acetate extract FC11 showed the strongest β-carotene–linoleic acid activity (IC50: 37.77 ± 2.11 μg/mL). The water extract FC24 showed the strongest AChE (IC50: 135.52 ± 0.77 μg/mL) and tyrosinase (IC50: 34.46 ± 1.05 μg/mL) inhibition. The results demonstrated that both harvesting season and extraction solvent significantly influenced the phytochemical composition and biological activities. Principal component analysis revealed clear discrimination among extracts, and molecular docking supported these findings by highlighting strong interactions of hesperidin and rutin with target enzymes. PCA explained 50.30% of the total variance. Molecular docking analysis revealed the strongest binding affinities for hesperidin toward AChE (−9.3 kcal/mol), hesperidin and rutin toward BChE (both −10.8 kcal/mol), and rutin toward tyrosinase (−10.3 kcal/mol). ADMET predictions suggested favorable oral drug-likeness for selected compounds, whereas others may require further optimization. Overall, these findings indicate that F. carica leaves represent a promising source of natural phenolics with multifunctional bioactivity.
Oxidative stress is caused by the imbalance between the generation of free reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidant defense systems, which participate in animal growth, development, disease pathogenesis, and aging. This review summarizes endogenous and exogenous triggers of ROS/RNS overproduction, as well as model animals and cell models together with oxidative stress biomarkers and detection methods. We further dissect the three-layered redox regulatory network, focusing on crosstalk among four core pathways (Nrf2-ARE, NF-κB, MAPK, PI3K/Akt) that govern cell fate via oxidative eustress or distress. Excessive ROS/RNS trigger irreversible DNA damage and metabolic disorders, leading to inflammation and apoptosis. Finally, we prospect integrating non-model animals and multi-omics to advance oxidative stress research. This work provides a comprehensive theoretical framework for animal redox biology studies.
Long-term injury surveillance in professional football is essential for understanding temporal changes in injury patterns. However, prospective studies spanning multiple consecutive seasons within the same professional club remain scarce. This study aimed to investigate injury epidemiology, temporal trends, and injury characteristics over nine consecutive seasons in an elite Croatian professional football club. This retrospective longitudinal study over nine competitive seasons (2015/16–2023/24) included 167 male players participating in the professional first-team environment from a single professional football club, contributing a total of 382 player-seasons across nine consecutive seasons. A total of 749 time-loss injuries were recorded according to the FIFA Medical Assessment and Research Centre (F-MARC) consensus recommendations. Temporal trends were evaluated using Joinpoint regression, while injury characteristics, anatomical distribution, tissue involvement, and injury burden were analysed descriptively. Overall injury incidence averaged 12.66 injuries per 1000 h of exposure (95% CI: 11.77–13.60), with substantially higher incidence during matches (50.13 injuries/1000 h) than training (7.97 injuries/1000 h). Joinpoint regression identified a non-significant annual decline in injury incidence before the COVID-19 season (2019/2020) (APC = −9.66%), followed by a non-significant increase thereafter (APC = 4.88%). At least one injury was recorded in 295 player-seasons, corresponding to 77.2% of all eligible player-seasons. More than 80% of all injuries involved the lower extremities, while muscle injuries accounted for almost half of all recorded injuries. Functional muscle disorders were the most frequent injury type, whereas meniscal and articular cartilage injuries were associated with the highest mean time loss per injury. The predominance of lower-limb muscle injuries, together with the substantial burden associated with less frequent intra-articular knee injuries, highlights key priorities for injury prevention in professional football. Long-term surveillance within the same club provides valuable insights into evolving injury patterns and supports the development of targeted strategies to maximise player availability.
Chronic pain is highly prevalent among older adults and represents a major health challenge due to its multifactorial aetiology, association with multimorbidity and frailty, and impact on quality of life. This narrative review synthesises evidence from the last few decades addressing chronic pain in older adults, with emphasis on risk factors, underlying mechanisms, and preventive strategies. Risk factors were organised according to the Dahlgren and Whitehead “Rainbow model” into individual, environmental, and social determinants. Individual-level factors—particularly physical inactivity, abnormal body weight, poor nutrition, mental health disorders, maladaptive pain beliefs, sleep disturbance, previous surgical and postoperative pain, multimorbidity, frailty, smoking, and alcohol use—were associated with pain persistence. Emerging evidence related to environmental and social determinants, including reduced nature and sunlight exposure, low socio-economic status, occupational factors, and social isolation, suggests further increased pain vulnerability. Mechanistic evidence indicates that ageing is associated with impaired descending pain modulation and increased susceptibility to peripheral and central sensitisation. Although randomised preventive trials in older adults remain scarce, converging evidence suggests that targeted lifestyle modification, early pain management, and multimodal non-pharmacological strategies may reduce progression to chronic pain. A prevention-oriented, risk-stratified approach integrating clinical care with broader public health strategies may help mitigate the growing burden of chronic pain in ageing societies.
