Search Results (13,700)

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. The dysregulation of Sox9 during chondrogenesis leads to a skeletal malformation termed campomelic dysplasia and has emerged as a significant factor in various other human diseases, including cancer. A point mutation at position 76 (alanine to glutamic acid, A76E) of Sox9 is recognized as one of the causes of campomelic dysplasia. We have used a combination of biophysical, structural and computational techniques to characterize the Sox9 A76E mutant and compare it with the wild-type (WT) Sox9. WT and A76E Sox9 assemble as homodimers, but form predominantly monomeric complexes in the presence of Sox-specific DNA. A CD analysis shows that the A76E mutant preserves the folding as well as the overall secondary structure of Sox9. Both A76E and WT Sox9 behave similarly in the presence of Sox-specific DNA. Perturbation, with increased temperature, displays a lower melting point for A76E, relative to WT Sox9, indicating decreased stability that may arise due to the long and charged side chain of glutamic acid compared to the small hydrophobic alanine, making unfavorable intra-molecular interactions. The destabilizing effect of the A76E mutant may disturb the formation of a stable higher-order complex that is a prerequisite for normal gene expression. Full article

Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide analogs of the classical NSAIDs (NSI-1–NSI-9) were developed and synthesized to mask the carboxylic acid moiety and minimize COX-induced adverse effects while maintaining anticancer activity. The cytotoxic effect of such substances has been demonstrated in some leukemia cell lines (HL-60, MV4-11, KG1a, and K562). NSI-5 exerted the highest anti-leukemic activity among these sulindac analogs, as determined at a sub-micromolar level in all cell lines studied, by IC50. This mechanistic data also demonstrated that NSI-5 induced apoptosis that was dose-dependent, especially in HL-60 cell lines, and increased the sub-G1 cell fraction. This apoptotic process was also accompanied by a significant decrease in mitochondrial membrane potential, which is characteristic of the induction of the intrinsic apoptotic process. Interestingly, NSI-5 decreased the intracellular reactive oxygen species (ROS) and the expression of most antioxidants (catalase and glutathione synthetase), as well as the redox balance. Gene characterization in vitro also suggested activation of apoptotic pathways, where expression of Bax, Bak1, and Caspase-3 increased, suggesting a potential p53-independent apoptotic pathway, in contrast to control for Bcl-2 expression. Collectively, these findings indicate that NSI-5 is a promising in vitro anti-leukemic lead compound, with activity associated with mitochondrial dysfunction and altered redox regulation. The observed effects are consistent with previously reported COX-independent activity of structurally related NSAID derivatives, and support further investigation of NSI-5 in preclinical models. Full article

Background: Shikonins are natural naphthoquinones that exhibit a range of biological activities. They are typically extracted using nonpolar solvents; however, green extraction approaches remain underexplored. Methods: Phytochemical profiling of E. vulgare root extracts was performed using HPLC-ESI-QTOF-MS/MS and quantitative analysis using HPLC-PDA. Shikonin extraction was performed using VNADESs based on thymol, camphor, menthol and benzyl alcohol. The feasibility of removing the VNADES from the extracts via freeze-drying was assessed. The cytotoxic, antioxidant, anti-inflammatory and antimicrobial activities of the hexane extract and the selected VNADES-based extract (TBa 2:8) were compared. Results: Eight shikonin derivatives were identified in the extracts. VNADES extracts contained comparable amounts of shikonin to hexane extracts; however, freeze-drying resulted in significant shikonin content loss. TBa 2:8 extract exhibited noticeably lower cytotoxicity than the hexane extract while its antioxidant potential depended on the assay applied. In contrast to the hexane extract, TBa 2:8 demonstrated the ability to reduce intracellular ROS and NO levels. However, the hexane extract exhibited stronger antimicrobial activity. Conclusions: VNADES systems enable efficient extraction of shikonin derivatives with performance comparable to hexane. Although the resulting extracts exhibit multidirectional biological activity, it remains challenging to remove the VNADESs effectively without losing the shikonins. Full article

Aggregation and seeded propagation of α-synuclein (α-syn) are central to the pathogenesis of Parkinson’s disease and related synucleionopathies. Modulation of seeded aggregation and amplification of pathological α-syn species represents a promising strategy for limiting disease progression. Here, we investigated the effects of naturally derived polyphenolic compounds on α-syn fibrillation, seeded aggregation, and associated cytotoxicity. Among the compounds examined, salvianolic acid B and dihydromyricetin exhibited significant inhibitory effects on α-syn aggregation. Biochemical and biophysical analyses using Thioflavin-T fluorescence, Congo Red binding, and transmission electron microscopy demonstrated that both compounds inhibited fibril formation and altered fibril morphology. Notably, dihydromyricetin efficiently disaggregated preformed fibrils and suppressed seeded fibril elongation, whereas salvianolic acid B primarily delayed aggregation kinetics. Both compounds significantly reduced α-syn-induced cytotoxicity in BE(2)-M17 cells. These findings demonstrate that salvianolic acid B and dihydromyricetin differentially modulate key steps in the α-syn aggregation pathway and reduce associated cellular toxicity. Collectively, these results provide mechanistic insight into the modulation of seeded α-syn aggregation and identify salvianolic acid B and dihydromyricetin as effective modulators of pathological α-syn assembly. Full article

Introduction: Low back pain (LBP) is the leading cause of disability worldwide, with substantial variation in prevalence across regions. It is associated with a wide range of biophysical, psychological, social, and lifestyle factors, as well as comorbid conditions. Given its high impact, identifying population-level correlations of LBP is essential for informing prevention strategies. This study aimed to assess demographic, socioeconomic, lifestyle, and health-related factors associated with LBP in Hungary. Methods: A repeated cross-sectional analysis was conducted using secondary data from three waves of the European Health Interview Survey (EHIS) carried out in Hungary in 2009, 2014, and 2019. Results: The prevalence of LBP increased over the study period. Female sex, higher educational attainment, normal body mass index, non-smoking status, abstaining from alcohol, and good self-perceived health were associated with lower odds of LBP. In contrast, older age (≥65 years), unfavorable financial status, residence in socioeconomically disadvantaged regions, use of over-the-counter medications, and several chronic conditions were associated with higher odds. Conclusions: Reducing the impact of low back pain requires its integration into comprehensive public health frameworks that combine chronic disease management with consideration of socioeconomic inequalities at the population level. Full article

Background/Objectives: Cytokine-mediated immune dysregulation contributes to the heterogeneity of multiple sclerosis (MS). Interleukin-18 (IL-18) and interleukin-8 (IL-8) are involved in distinct inflammatory pathways; however, their genetic contributions to disease susceptibility and radiological activity remain incompletely defined. Methods: In this study, 98 relapsing–remitting MS (RRMS) patients and 98 healthy controls were genotyped for IL-18 and IL-8 variations using PCR-based methods. Clinical data and MRI findings were analyzed in the MS cohort. Associations with disease susceptibility, clinical severity (EDSS), and MRI activity were evaluated using regression analyses. Results: IL-18 (−137 G/C) and IL-8 variations were significantly associated with MS susceptibility. The G allele of IL-18 (−137), the T allele of IL-8 (−251), and the C allele of IL-8 (+781) were more frequent in MS patients. No significant associations were observed between cytokine variations and clinical severity measures. However, IL-18 (−137) variation was significantly associated with higher baseline MRI lesion burden, with C allele carriers showing increased lesion counts. In addition, IL-8 (−251 AA genotype) was independently associated with increased annual lesion development. These findings were confirmed in multivariable regression analyses. Conclusions: IL-18 and IL-8 gene variations contribute to MS through distinct but complementary mechanisms. IL-18 appears to be primarily involved in disease susceptibility and baseline inflammatory burden, whereas IL-8 is more closely associated with ongoing radiological activity. These results highlight the importance of integrating genetic and imaging biomarkers to better understand disease heterogeneity in MS. Full article

Accurate crop classification in complex and heterogeneous agricultural landscapes is often challenged by mixed-pixel effects and spatial autocorrelation. This study proposes a prior-guided crop classification framework that integrates accessible Moderate Resolution Imaging Spectroradiometer (MODIS) optical and Sentinel-1 synthetic aperture radar (SAR) time-series data with explicit phenological and structural priors. By embedding physically meaningful constraints into temporal feature learning, the model shifts from purely data-driven learning toward biophysically interpretable discrimination between crop types and background classes. Performance was rigorously evaluated using spatial cross-validation (SCV) to ensure geographic independence. Results demonstrate that the prior-guided CNN achieves an overall accuracy (OA) of 98.66% and a Kappa of 0.9832, outperforming unguided deep learning and conventional machine learning models. Notably, the framework exhibits high spatial robustness, with a minimal performance gap between random and spatial validation (ΔOA = 0.0049). In addition to improving classification accuracy, integrating phenological features with SAR-based prior information enhances the stability of non-crop categories in fragmented scenarios, while leveraging readily available medium-resolution data to support large-scale applications. These findings demonstrate that embedding physically meaningful prior knowledge into multi-source time-series learning improves classification accuracy while enhancing spatial generalizability and interpretability. More broadly, the proposed framework offers a transferable paradigm for integrating domain knowledge with deep learning, providing a practical and scalable solution for crop mapping in heterogeneous agricultural landscapes using widely accessible medium-resolution data. Full article

Petroleum contamination of soils remains a significant environmental problem in boreal regions, where low temperatures constrain natural attenuation processes and complicate bioremediation. Nitrogen biostimulation is widely used to enhance petroleum hydrocarbon degradation; however, the combined effects of temperature regime, nitrogen form, contamination level, and nitrogen dosage remain insufficiently resolved for sandy podzolic soils of northern regions. This study investigated nitrogen-assisted biostimulation of petroleum-contaminated sandy podzolic soil collected in the Khanty–Mansi Autonomous Okrug (Western Siberia, Russia) using a factorial experimental design. Soil samples were artificially contaminated with crude oil at concentrations of 25, 50, and 100 g kg⁻¹ and incubated under warm and cold temperature regimes. Two nitrogen sources, urea and ammonium nitrate, were applied at several dosages. Changes in residual petroleum hydrocarbon content were monitored together with the abundance of culturable microorganisms under the applied cultivation conditions at the intermediate contamination level on day 60. Nitrogen supplementation enhanced petroleum hydrocarbon removal relative to the untreated control, but the magnitude of the effect depended substantially on temperature, nitrogen form, and contamination level. Under the tested conditions, ammonium nitrate was generally associated with stronger hydrocarbon removal than urea, particularly at the intermediate contamination level (50 g kg⁻¹). The results indicate that the response to nitrogen biostimulation in sandy boreal soils is controlled by interacting experimental factors rather than by nitrogen addition alone. These findings improve the positioning of nutrient-assisted remediation in cold-region soils and provide a basis for future mechanistic and field-scale studies. Full article

Leaf Area Index is a crucial biophysical variable, and its accurate estimation is essential for understanding vegetation dynamics. However, cloud cover significantly restricts optical remote sensing, hindering the generation of spatially continuous Leaf Area Index products. Remote sensing foundation models offer novel solutions to this challenge. This study presents an end-to-end framework based on the fine-tuned Prithvi foundation model for direct LAI retrieval from cloud-contaminated 30 m Harmonized Landsat and Sentinel-2 imagery. By mapping inputs directly to Hi-GLASS reference labels, the proposed architecture processes cloud contamination and vegetation signals simultaneously and circumvents the error propagation inherent in cascaded retrieval pipelines. Results demonstrate that the end-to-end LAI retrieval model significantly outperforms cascaded variants, achieving a superior R² (0.78) and lower RMSE (0.57). Furthermore, predictive accuracy exhibits a distinct U-shaped trajectory relative to the temporal mean cloud fraction, reaching an inflection point at 50–60% occlusion, which highlights the model’s implicit regularization capacity under severe atmospheric interference. This work establishes that direct feature learning with foundation models offers a more robust and streamlined pathway for generating continuous biophysical products from imperfect optical observations, prioritizing quantitative fidelity over artificial perceptual sharpness. Full article

Urban green spaces provide essential ecosystem services, yet mismatches between subjective perceptions and objective assessments may constrain effective planning. This study examines the correspondence between perceived and measured ES across two contrasting urban green spaces in Shanghai: Century Park, a managed urban park, and Sanlin Green Space, a naturalistic urban forest. Objective ecosystem services (regulating, supporting, and cultural) were quantified using UAV-based biotope mapping and indicators including biophysical metrics (Net Primary Production, Water Retention, PM10 removal, and Land Surface Temperature), structural diversity indices (Shannon Diversity of land cover, vegetation, and tree structure), and visual–spatial proxies (Green View Index, Sky View Index, Water View Index, color metrics, and spatial openness). Subjective perceptions were derived from panoramic image-based questionnaires, with perception scores predicted using XGBoost and aggregated via SHapley Additive exPlanations (SHAP). Correlation analyses, spatial regression models, and partial least squares structural equation modeling were applied to explore relationships and pathways. Results show weak but significant positive associations in the urban park, whereas no overall correspondence was observed in the urban forest. Spatial mismatches were concentrated in biotopes with distinctive visual–ecological features and in fragmented areas. Green View Index is associated with higher perceptions in both sites, while the Sky View Index reduced perception in the forest context. These findings highlight strong context dependence in perceived–measured ecosystem service relationships and underscore the importance of integrating ecological structure and visual legibility in the design and management of the studied urban green spaces in Shanghai. Full article

Structurally complex plasmonic nanoarchitectures represent an emerging class of nanomaterials with properties that extend beyond those of conventional spherical nanoparticles. Their distinctive structural motifs generate dense near field electromagnetic hot spots, expand interfacial surface area, and create biophysical environments at the nano–bio interface that can actively engage cellular signaling networks relevant to neural regeneration and aging. Despite growing interest in these platforms, a systematic, omics-guided synthesis that links nanoparticle structural features to transcriptomic programs and regenerative outcomes has been lacking. In this review, we summarize recent advances in high complexity plasmonic nanoparticle engineering and integrate published omics-based evidence of their cellular effects, organizing the discussion. Across these studies, transcriptomic analyses of nanoparticle treated neural systems consistently highlight three convergent biological themes: mitigation of oxidative stress and activation of antioxidant pathways, suppression of neuroinflammatory signaling, and induction of neuronal developmental and plasticity programs. Collectively, the omics-guided findings synthesized here suggest that structural complexity in plasmonic nanoarchitectures is not merely a synthetic achievement but a tunable determinant of cellular state, with important implications for the rational design of regenerative nanomedicines targeting neurodegenerative diseases and age-related neuronal decline. Full article

Doxorubicin is an effective chemotherapeutic agent, but it causes gastrointestinal toxicity that impairs treatment efficacy and quality of life. This study investigated the effects of liraglutide, a GLP-1 analog, on acute doxorubicin-induced gut toxicity in rats. Sixty male Wistar rats were assigned to four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). Groups L and DL received liraglutide (0.6 mg/kg, s.c.) for two weeks. D and DL were given a single dose of doxorubicin (20 mg/kg, i.p). After 48 h, the distal colon, feces, and blood were collected. Results: Doxorubicin caused crypt disruption, goblet cell loss, apoptosis, and reduced fecal short-chain fatty acids. Levels of TNF-α, NF-κB, Bcl-2, TLR4, and antioxidant enzymes were unchanged among groups. Microbiota analysis showed similar α-diversity but altered β-diversity. Doxorubicin reduced Bacteroidetes and increased Proteobacteria, with higher Arcanobacterium and Clavibacter genera abundance. Liraglutide alone decreased Bacteroidetes and increased Corynebacterium and Actinobaculum genera. Combined treatment showed no significant effects. We conclude that acute doxorubicin administration induces intestinal structural damage, reduces short-chain fatty acids, and changes microbiota composition. Although liraglutide alters microbial profiles, it does not attenuate doxorubicin-induced gut toxicity. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyrimethamine (PYR) as an NRF2 inhibitor and demonstrated that inhibition of dihydrofolate reductase (DHFR) represents the primary mechanism underlying its NRF2-suppressive activity, supporting its advancement into a Phase I window-of-opportunity clinical trial (NCT 05678348). Meanwhile, in NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells, PYR promoted NRF2^Mut ubiquitination and proteasomal degradation and shortened its half-life. This study aims to explore additional modes of action by which PYR inhibits NRF2. Methods: Cell cycle analysis was performed by flow cytometry. Cell proliferation, apoptosis and chemosensitivity were assessed by Live-Cell Analysis System, while radiosensitivity was evaluated using X-ray irradiation and the CellTiter-Glo assay. Molecular interactions between NRF2 and KEAP1 were examined through Co-IP and PLA, and the direct binding of PYR to KEAP1 was quantified using ITC and SPR. Molecular docking and dynamic simulations were employed to predict potential PYR-binding pockets within the Kelch domain. Results: Using genetically defined isogenic ESCC cell models, we show that activation of mutant NRF2 (NRF2^Mut) or wild-type NRF2 (NRF2^WT) produces distinct, context-dependent effects on squamous differentiation, proliferation, and therapeutic response. We further demonstrate that PYR restores sensitivity to chemotherapy and ionizing radiation in NRF2^Mut ESCC cells. Mechanistically, short-term PYR treatment promotes KEAP1-dependent proteasome-mediated degradation of NRF2^W24C. Biochemical and biophysical assays indicate that PYR enhances the interaction between KEAP1 and NRF2^W24C in a manner associated with KEAP1-dependent proteasomal degradation. Computational modeling further suggests that PYR may engage a pocket within the Kelch domain to facilitate the NRF2^W24C-KEAP1 interaction. Conclusions: These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2^Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2–KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2^Mut cancers, including ESCC. Full article

Acrylamide is a neurotoxic compound formed during thermal food processing that can cross the placental barrier and potentially affect fetal brain development. This study aimed to evaluate the effects of maternal acrylamide exposure on parvalbumin-immunoreactive (PV-IR) neurons in the pyramidal layer of the subiculum (Sub) and hippocampus of weaning rats. Pregnant Wistar rats received 3 mg/kg b.w. of acrylamide orally for 5 or 10 days during the prenatal period. After weaning, offspring brains were analyzed using immunohistochemistry, morphometry, and quantitative assessment of PV-IR neuron density and staining intensity in the pyramidal layers of the Sub, Cornu Ammonis 1 (CA1), and Cornu Ammonis 3 (CA3). The results demonstrated a significant increase in PV-IR neuron density in the Sub and CA1 after prolonged maternal exposure, accompanied by a predominance of weakly stained cells and decreased mean immunostaining intensity. Morphometric analyses revealed region-specific changes: enlarged cell area and perimeter with reduced nuclear-to-cytoplasmic ratio in the Sub, whereas CA1 and CA3 showed smaller cell dimensions and altered shapes. In conclusion, maternal acrylamide exposure is associated with region-dependent alterations in the morphology and immunoreactivity of PV-IR neurons within the offspring hippocampus. Full article

Bilirubin, historically recognized solely as a waste product of heme catabolism, has recently gained attention for its potential protective role in the cardiovascular system. Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the heart against oxidative stress, ischemia–reperfusion injury, and the progression of cardiovascular diseases, such as heart failure. As an endogenous hormone, bilirubin activates peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that controls energy balance and lipid metabolism. Moderately elevated circulating bilirubin levels have been associated with a reduced risk of coronary artery disease, heart failure, and myocardial infarction; however, the mechanisms underlying bilirubin’s protective effects remain incompletely understood. Conversely, the gut microbiota’s metabolism of bilirubin to urobilin is detrimental, given urobilin’s association with cardiometabolic dysfunction. The therapeutic potential of bilirubin in the management of cardiovascular disease is becoming increasingly apparent, supported by preclinical research and emerging technologies that enhance bilirubin delivery via nanoparticles and methods to elevate plasma bilirubin levels. Collectively, these scientific advancements position bilirubin as a promising, biologically plausible endogenous therapeutic for the prevention and treatment of heart disease. Full article