Search Results (20,109)

Background/Objectives: The health-protective properties of olive oil phenolics, including their potential chemopreventive and anticancer effects, have attracted considerable scientific interest. However, their in vivo efficacy and mechanisms of action remain insufficiently understood. Recent advances in extraction and purification technologies have enabled large-scale production of highly purified olive oil phenols and phenolic-rich extracts, facilitating translational research. Methods: Herein, the antitumor efficacy of isolated olive oil phenols and phenolic-rich formulations was investigated in an MDA-MB-231 triple-negative breast cancer (TNBC) xenograft model. Results: Intraperitoneal administration of oleocanthal (OLC), oleuropein aglycone (OleA) or their combination reduced endpoint tumor burden, with OLC exhibiting the most pronounced effect. Oral administration of total olive oil phenolics (OOPs) achieved comparable efficacy. Pre-treatment initiated before tumor cell implantation conferred the greatest protection, consistent with a prophylactic mode of action. In contrast, delayed intervention displayed diminished or no antitumor benefit. Phenolic-rich extra virgin olive oil likewise showed an inhibition trend in tumor progression. Mechanistically, OOPs attenuated plasma protein oxidation, modulated proteasome mediated proteolysis, and reduced γH2AX levels in vivo. Furthermore, OOPs negatively affected the MDA-MB-231 cell migration in a concentration-dependent manner in vitro. Conclusions: Collectively, these findings are consistent with antitumor activities of olive oil phenolics via multiple mechanisms and support their further investigation as prophylactic agents in TNBC and as nutraceuticals. Full article

Background/Objectives: Novel (immune) therapies are needed to stabilize the disease or achieve remissions in AML. We already demonstrated that DCleus can be generated ex vivo from AML patients’ blasts in WB using approved drugs (GM-CSF and PGE-1 (Kit-M) or GM-CSF and Picibanil (OK-432), Kit-I). The generated DCleus induce antileukemia-directed immune cells of the adaptive and innate immune system, enabling leukemia-specific immune activation after MLC. Methods: We compared the effects of Kit-I vs. Kit-M by quantifying (1) their potential to produce DCs/DCleus from WB samples from 6 healthy individuals and 28 AML patients’ WB in different stages of the disease and (2) the activation of adaptive and innate leukemia-specific IFNγ-producing or degranulating antileukemic cells after MLC with and without Kit-I/Kit-M-pretreated WB. Furthermore, we correlated the obtained results with the achieved improved cells’ antileukemic functionality and patients’ clinical data. Results: In AML samples we found significantly higher frequencies of (mature) DCleus generable without induction of blast proliferation in Kit-M as well as (although less pronounced) in Kit-I-treated vs. untreated samples, a significant increase in the frequency of (leukemia- specific) immunoreactive cells, and improved blast cytotoxicity after MLC with Kit-M and with Kit-I-treated vs. untreated samples (potentially with higher induction of CD4 and CIK IFNγ + cells in Kit-I-pretreated samples). These data might suggest that both Kits work via different pathways. Conclusions: We show that Kit-M and Kit-I produce DCs/DCleus and subsequently enhance (potentially via a different mode of action) antileukemic immune cell activation after MLC. Our findings point to a possibility to enhance antileukemic treatment in vivo by combining agents or identifying criteria for selecting an appropriate agent (combination) for the respective patient in the course of a personalized treatment strategy. Full article

Background/Objectives: Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in haematological malignancies but has shown limited efficacy against solid tumours. Key barriers include inadequate tumour trafficking, immunosuppressive tumour microenvironments, poor selectivity and heterogeneity of antigen expression, and challenges related to safety and manufacturing. Biomaterial-based technologies have emerged as a potential strategy to address many of these limitations. This review aims to critically evaluate biomaterial approaches designed to enhance CAR-T cell therapy of solid tumours and assess their translational potential. Methods: A narrative review of recent pre-clinical translational studies was conducted, focussing on biomaterial platforms developed to improve CAR-T cell delivery, persistence, functionality, safety control, and manufacturing efficiency in solid-tumour settings. Approaches were analysed according to their mechanisms of action, therapeutic benefits, and stage of translational readiness. Results: Biomaterial strategies, including nanoparticles, injectable and implantable hydrogels, scaffolds, and hybrid delivery systems, have improved CAR-T infiltration, survival, and therapeutic efficacy in several solid-tumour models. Localised delivery of cytokines and other immunomodulatory cues enabled improved spatio-temporal control of CAR-T activation, reducing systemic toxicity, and increasing persistence. Additional applications include amplified ex vivo CAR-T expansion and support for non-viral or in vivo CAR-T generation. However, increased material complexity was frequently associated with challenges in scalability, regulatory approval, and long-term safety. Conclusions: Biomaterial-enabled approaches offer a versatile toolkit to address key biological and translational barriers limiting CAR-T cell therapy of solid tumours. Strategies based on clinically familiar materials and simplified designs appear most suitable for near-term clinical translation, emphasising the need to balance engineering innovation with safety, scalability, and integration into existing clinical workflows. Full article

The primary pathogenic mechanism of Type I hypersensitivity reactions involves histamine-mediated activation of the H1 receptor (H1R) and the subsequent signaling of the phospholipase C β-inositol trisphosphate (PLCβ-IP₃) pathway. The present study evaluates the in vitro efficacy of a novel nutraceutical mixture—Quercetin, Perilla frutescens, Boswellia serrata, Blackcurrant, Parthenium, Helichrysum, Lactobacillus Acidophilus (L. acidophilus) and Bifidobacterium animalis (B. animalis)—in modulating HRH1 gene expression and the activation of the intracellular second messenger inositol trisphosphate (IP₃). Quantitative PCR (qPCR) analysis revealed that the mixture downregulated HRH1 expression by approximately 33% (p < 0.05) compared to the control group. Furthermore, ELISA assays demonstrated that the mixture significantly reduced IP₃ release by 10.30% (p < 0.05 vs. positive control). These results indicate that the nutraceutical mixture exerts its effects by modulating the H1R-PLCβ-IP₃ pathway through the reduction in both H1 receptor gene expression and IP₃ release. These findings suggest a potential mechanism of action involving the modulation of the histamine H1 receptor. Consequently, the mixture emerges as a promising candidate for further investigation into the H1R-IP₃ activation cascade. Full article

Dual-protein systems combining whey protein isolate (WPI) and soy protein isolate (SPI) offer complementary nutritional benefits but are limited by the presence of major allergens. Lactic acid bacteria (LAB) fermentation provides a promising strategy to mitigate this limitation. In this study, Lacticaseibacillus paracasei JM053, selected from 13 LAB strains based on phenotypic screening, significantly reduced the in vitro allergenicity of the dual-protein system, increasing the IgE-binding inhibition rate to 48.75%. Whole-genome sequencing and characterization of JM053 revealed a comprehensive proteolytic system, including the proline-specific peptidase genes pepX and pepQ, which may contribute to the degradation of allergenic peptide sequences. Combined with in silico bioinformatic analysis, potential cleavage sites within the linear epitopes of the dual-protein system were predicted based on the substrate specificity of the identified proteases, offering a testable hypothesis for the strain’s mechanism of action. In addition, in vitro safety assessment and genomic analysis supported the safety potential, stress tolerance, and probiotic characteristics of JM053. Collectively, this study provides a valuable candidate strain for the development of hypoallergenic dual-protein products and offers preliminary genomic insights into LAB-mediated allergenicity reduction. Full article

Pyridopyrimidine is an important heterocyclic scaffold widely explored in anticancer drug discovery. Its structural similarity to purine enables effective interaction with various biological targets, mainly kinases involved in cancer progression. This manuscript presents recent developments reported between 2021 and 2026, focusing on the biological evaluation, and structure–activity relationships of pyridopyrimidine derivatives. Many of these synthesized compounds act as inhibitors of key targets such as EGFR, CDK4/6, and the PI3K/mTOR pathway, which are closely associated with tumor growth, survival, and resistance mechanisms. Other targets such as ATR and PIM are also explored. Recent studies show that structural modifications, including substitution on the core ring and hybridization with pharmacologically active moieties like triazoles and thiazolidinediones, significantly improve anticancer activity. Several derivatives have demonstrated strong antiproliferative effects against different cancer cell lines and are capable of inducing apoptosis and cell cycle arrest. In addition, molecular docking and other computational studies support their binding efficiency and help explain their mechanisms of action. There is also increasing interest in the development of dual-target or multi-target inhibitors to overcome drug resistance and enhance therapeutic effectiveness. Overall, pyridopyrimidine- and pyridopyrimidinones-based compounds continue to show great promise as potential anticancer agents. Further research combining synthetic chemistry, biological studies, and computational approaches may lead to the development of more effective and safer drugs in the future. Full article

Addressing the current issues of the uncertain primary frequency bands and the difficulty in directly measuring the spectral characteristics of neural electromagnetic signals transmitted within nerve fibers, this study investigates the spectral and time-domain properties of the neural electromagnetic signals through finite element simulations, using the influence of the node of Ranvier on nerve conduction velocity as a breakthrough point, and develops a coaxial transmission line impedance transformation model. The research results demonstrate that the primary signals capable of effective transmission within nerve fibers may reside in the terahertz (THz) band. They also show that the node of Ranvier essentially functions by regulating its geometric length to achieve impedance matching between the node and the myelin sheath, thereby reaching the optimal efficiency for signal coupling. The above finding not only explains the mechanism underlying the non-monotonic variation in neural conduction velocity with the length of the node of Ranvier, but also provides the latest perspective for understanding the relationship and differences between transmembrane action potentials that accompany the generation of neural signals and information transmission carriers—electromagnetic signals. It may also provide a theoretical supplement to the understanding of signal frequency–timing issues in neural encoding. Full article

Comparative welfare research studies social protection within national regimes and asks how responsibility is shared between the state, the market and the family. That perspective captures only part of transnational family life. Families living across borders need to bring together income, care and practical knowledge while also dealing with different legal and institutional settings. This study develops two connected ideas—social corridors of migration and family decommodification potential—and examines them through an integrative synthesis of research with a focus on Central and Eastern Europe (CEE). Greater security for one person may rest on another person’s action in the form of either unpaid care or continuing labour-market dependence. Family decommodification potential is therefore regarded as both conditional and sensitive to how benefits and costs are distributed within the family. Full article

Modern energy systems, including those supporting transportation electrification, are increasingly exposed to volatile market conditions and external events. Effective decision-making therefore requires the integration of structured operational data with unstructured contextual information. Existing studies on Large Language Model (LLM)-assisted energy systems have mainly applied LLMs to individual tasks such as forecasting, scheduling, or decision support, while forecasting and control are typically treated separately. As a result, semantic information extracted from external events is not consistently propagated from market prediction to operational decision-making. This paper proposes a unified dual-stage framework in which the LLM functions as a shared semantic information processor, converting raw event data into structured representations used by both forecasting and control modules. In the forecasting stage, these representations improve price prediction under non-stationary conditions. In the control stage, the same information provides an event-aware contextual action prior for reinforcement learning-based energy management. This design allows external event information to inform both future-state estimation and subsequent control decisions, establishing a consistent connection between prediction and decision-making. The framework is evaluated using real-world electricity market data and a battery energy management environment. The results show that the proposed framework achieves the highest average cumulative reward among the evaluated methods while maintaining greater robustness than the forecasting-only LLM configuration. Overall, this work demonstrates the benefit of consistently propagating structured semantic information across forecasting and control and provides a viable approach to event-aware intelligent energy management, with potential extensions to multi-energy transportation systems and electrified mobility applications. Full article

Wood vinegar (WV), also known as pyroligneous acid, is the aqueous condensate produced during lignocellulosic biomass pyrolysis, generated alongside biochar and non-condensable gases. In forest biorefineries, it represents a promising value-added coproduct capable of transforming forestry and agroforestry residues into a multifunctional bioproduct. Its composition, dominated by water, organic acids, phenolic compounds, aldehydes, and ketones, confers antimicrobial, antioxidant, biostimulant, herbicidal, and preservative properties. This review critically examines WV production, chemical composition, purification strategies, mechanisms of action, and applications, explicitly distinguishing evidence-based uses from prospective ones. Current evidence supports applications in agriculture, wood preservation, environmental management, and forestry, including forest nursery production and clonal propagation of Eucalyptus and Pinus. However, the literature remains fragmented by compositional variability, non-standardized terminology, limited mechanistic understanding, and scarce long-term toxicological and techno-economic assessments. WV holds significant potential for sustainable biomass valorization and circular bioeconomy strategies. Realizing this potential requires harmonized analytical protocols, standardized formulations, rigorous mechanistic studies, life-cycle assessments, and regulatory frameworks that support the transition of this heterogeneous pyrolysis byproduct into a reliable commodity within integrated forest biorefineries. Full article

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Purpose: This study investigates the structural pathways driving the startup potential of Generation Z students in Romania’s post-transition economy. It examines the sequential relationship between Entrepreneurial Mindset (EM), Entrepreneurial Intentions (EIs), and Entrepreneurial Behavior (EB), focusing on the mediating role of intentions in bridging the gap between cognition and action. Design/methodology/approach: Using a quantitative explanatory design, data were collected through a two-stage hybrid framework from a sample of 215 Romanian business students associated with the Hackathon Innovation Labs (HILs), selected via a non-probability purposive sampling method. Hypotheses were tested using Structural Equation Modeling (SEM) with maximum likelihood estimation, supported by Confirmatory Factor Analysis (CFA) to ensure statistical rigor. Findings: Results confirm that EM is a robust predictor of EI, which significantly drives EB, explaining 45.2% of its variance. The findings highlight that intentions fully mediate the relationship, suggesting that a growth-oriented mindset turns into firm intentions to overcome institutional and cultural barriers. Originality: This research applies a rigorous SEM framework to a cohort of digital natives in an underrepresented Eastern European emerging market. It integrates mindset as a foundational cognitive precursor and provides empirical evidence of the sequential path to entrepreneurial behavior. Research limitations/implications: The study is limited by its sample size and geographic focus on Romanian business students. Future longitudinal research should explore external contingency factors, such as access to capital and ecosystem support, to validate model generalizability. Practical and social implications: Higher education should shift toward experiential programs like HILs, embedding credit-bearing hackathons and micro-credentials to foster an entrepreneurial mindset. Socially, sustaining this momentum with structured mentorship bridges the intention–action gap, transforming Gen Z’s digital potential into tangible economic value for the post-transition ecosystem. Full article

Pseudomonas syringae pv. actinidiae (Psa) is the most destructive pathogen of kiwifruit, and the absence of curative measures makes the management of Psa-induced kiwifruit bacterial canker (KBC) particularly challenging. Elettaria cardamomum produces an essential oil (CAR) rich in bioactive compounds with demonstrated potential to act directly against Psa, but its mechanisms of action remain insufficiently explored. Here, we investigated CAR’s mode of action in plants with established mild KBC symptoms, and assessed its potential as a plant elicitor. In the in planta assay, CAR application (0.1% w/v, applied 7 days after inoculation) reduced KBC symptoms, with the strongest effect observed 14 days after treatment (DAT). However, CAR did not significantly affect oxidative stress biomarkers, antioxidant system, pigments and primary metabolism, or the expression of target genes related to systemic acquired resistance or salicylic acid and jasmonic acid pathways. For instance, Psa inoculation significantly upregulated PR1 (≈5.4-fold) and PR5 (≈4.3–5.5-fold), irrespective of CAR application. Complementary in vitro assays revealed a transient, phase-dependent antimicrobial activity of CAR: although the effect disappeared by 32 h in liquid-phase assay and no inhibition was observed under vapor-phase exposure, a strong reduction in Psa viable cells (79.7%) was observed after 8 h exposure in the liquid phase. This study demonstrates that CAR exerts a direct, albeit transient, antibacterial effect against Psa, conferring curative activity when applied to plants with mild KBC symptoms. Consequently, repeated applications may be required to maintain disease suppression, as CAR does not appear to induce a sustained preventive defense response in the host. Full article

Sepsis-associated acute lung injury (SALI) is characterized by disruption of the alveolar–capillary barrier, uncontrolled inflammation, oxidative stress, and impaired tissue repair. Ferroptosis and cellular senescence have emerged as potentially interacting stress-response programs that may jointly shape the progression of septic lung injury. Ferroptosis promotes epithelial and endothelial damage through iron-dependent lipid peroxidation, glutathione depletion, and impaired GPX4-mediated lipid repair. In parallel, senescence-associated remodeling may contribute to persistent cell-cycle arrest, senescence-associated secretory phenotype (SASP) production, endothelial dysfunction, and defective regenerative capacity. This review summarizes current evidence on the molecular and cellular crosstalk between ferroptosis and cellular senescence in SALI. Candidate regulatory intersections include context-dependent mitochondrial dysfunction, reactive oxygen species accumulation, iron dyshomeostasis, metabolic reprogramming, lysosomal dysfunction, DNA-damage responses, and stress-responsive pathways involving p53, NRF2, ATF4, STAT3, and FOXO1. Direct SALI evidence is currently strongest for ferroptosis-induced senescence-associated remodeling in pulmonary endothelial cells, whereas senescence-associated ferroptosis resistance is supported mainly by non-pulmonary models. Likewise, SASP-mediated paracrine ferroptosis in neighboring pulmonary cells remains insufficiently validated. We therefore propose an evidence-informed, temporally and cell-type-dependent ferroptosis–senescence framework in SALI, in which acute senescence-associated responses may coexist with ferroptotic injury, whereas persistent senescence-associated remodeling may contribute to defective repair and microenvironmental injury amplification. Targeting this axis through ferroptosis inhibition, restoration of endogenous antioxidant defenses, senotherapeutic modulation, and regenerative strategies may offer stage-informed therapeutic opportunities. Further time-resolved and cell-specific studies are required to define causal relationships and clinically actionable therapeutic windows. Full article

Background/Objectives: Patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are at high risk for severe disease and treatment-related complications and toxicities. Pharmacogenetic studies suggest that genetic variants can alter the response to several drugs critical to alloHCT outcomes, including tacrolimus and cyclophosphamide, potentially impacting toxicity and treatment outcomes. Methods: To assess the frequency of pharmacogenetic variants in AML/ALL patients undergoing alloHCT, we used a validated 11-gene pharmacogenetic panel in an exploratory descriptive study. We retrospectively genotyped 142 AML/ALL patients including two atypical chronic myeloid leukemia (aCML) patients, ≥18 years, who underwent alloHCT at our center between January 2020 and June 2024. Results obtained from 470 individuals in the Lifelines NEXT population cohort were used as controls. Results: Almost all patients carried at least one pharmacogenetic variant (97.2%), with a mean of 3.2 (standard deviation = 1.5) variants per patient. Variants known to influence tacrolimus metabolism (CYP3A4 and CYP3A5) were present in 26.8% of patients. Variants known to influence cyclophosphamide metabolism (CYP2B6, CYP2C9, CYP2C19) were present in 81.7% of patients. Variant frequencies did not significantly differ from controls. Conclusions: Actionable pharmacogenetic variants are highly prevalent in alloHCT-recipients. Future studies should investigate whether genotype-guided drug selection and dosing could improve outcomes in alloHCT recipients. Full article