Search Results (17,899)

Confronted with severe global challenges, including water scarcity, excessive use of chemical fertilizers and pesticides, and heavy metal contamination in soils, conventional agricultural technologies exhibit marked limitations in integrated water–fertilizer management and non-point source pollution control. Leveraging their excellent water retention capacity, intelligent sustained-release properties, and environmental responsiveness, hydrogels offer innovative solutions to advance sustainable agricultural development. This review comprehensively outlines the fundamental types, crosslinking mechanisms, and key functional properties of hydrogels, with a focused discussion on their agricultural deployment as high-efficiency soil conditioners, fertilizer vectors, and pesticide carriers; it deciphers the microscopic water-holding mechanisms under the tristate water model, delineates the divergent water-uptake and retention behaviors between ionic and non-ionic hydrogels, and clarifies the cyclic water-holding and release mechanisms of hydrogels during soil amelioration. Thise paper further synthesizes hydrogel-enabled environmental remediation applications, in which heavy metals and pesticide residues in soils and aquatic systems are removed via functional-group coordination adsorption or photocatalytic degradation; concurrently, hydrogels have been shown to activate plant systemic immunity through calcium-signaling pathways, thereby inducing broad-spectrum antiviral defense responses. Moreover, hydrogels can be integrated into precision agriculture frameworks to enable real-time monitoring of crop physiological status and to support targeted irrigation and fertilization management. This work also evaluates the role of hydrogels in promoting seed germination, root system development, crop metabolic regulation, and stress resilience, while introducing tailored application strategies across distinct plant growth stages. Their documented economic advantages include water conservation, enhanced crop yields, reduced dependence on synthetic fertilizers, and lower labor costs. Nevertheless, the large-scale implementation of hydrogels continues to face multifaceted challenges—particularly poor degradability and latent ecological risks, as conventional polyacrylamide (PAM)-based gels resist soil mineralization and retain potentially neurotoxic monomers, leaving a critical gap in multi-annual field data concerning their non-target interference with native soil aggregate evolution, pore distribution, and rhizospheric carbon–nitrogen footprints. Mechanistically, many hydrogels with tensile strengths below 1 MPa are highly susceptible to three-dimensional network collapse under high-salinity osmotic shock and tillage mechanical stress, exhibiting a precipitous drop in water retention after more than three wet–dry cycles due to deficient long-term structural stability. Compounding these technical gaps are elevated production costs and low farmer adoption, driven by the absence of texture-specific performance thresholds—such as an available water increment ≥ 40% for sandy soils—and the lack of established life-cycle cost models and farmer incentive mechanisms for bio-based hydrogels. Moving forward, hydrogel technology should pivot toward materials innovation and cost-reduction engineering to broaden its applicability, employ ≥3-year, multi-habitat regional trials to delineate ecological benefit–risk boundaries, and ultimately position hydrogels as pivotal enablers of sustainable, green agricultural paradigms. Full article

Immunonutrition continues to generate heterogeneous and often contradictory clinical outcomes, suggesting that nutrients do not exert fixed immunological effects but interact with the biological context in which they operate. Sarcopenic obesity (SO) represents a paradigmatic clinical model of this complexity, where chronic low-grade inflammation, mitochondrial dysfunction, anabolic resistance, metabolic inflexibility, and microbiota remodeling converge to compromise the adaptive capacity of integrated immunometabolic networks. We propose that this condition may be interpreted as a state of impaired immunometabolic plasticity, which may help explain the context-dependent variability of nutritional responses. Within this perspective, micronutrients are viewed not simply as cofactors supporting immune competence but as dynamic regulators of interconnected immunometabolic pathways. Particular attention is devoted to vitamin D and resveratrol, presented as complementary regulators of immunometabolic plasticity. Within the proposed framework, vitamin D may contribute to immunometabolic competence, whereas resveratrol may act as a broader signaling modulator through the SIRT1/AMPK–PGC-1α axis, influencing mitochondrial function, inflammatory tone, metabolic flexibility, and epigenetic adaptation. Beyond isolated compounds, bioactive-rich food matrices, exemplified by Opuntia ficus-indica, are discussed as examples of systems-level modulators capable of coordinating inflammatory, metabolic, redox, and microbiota-dependent biological circuitry. This review introduces immunometabolic plasticity as a conceptual framework linking nutritional signals to the coordinated regulation of immune and metabolic adaptation across diverse biological contexts. Finally, we discuss how biomarker-guided phenotyping, multi-omics integration, and context-aware nutritional interventions may provide a foundation for precision immunonutrition, shifting the field from generalized supplementation strategies toward restoration of adaptive immunometabolic resilience. Full article

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular mechanisms of action remain to be determined. Therefore, this study aimed to systematically identify the active hypolipidemic constituents of M. folium and elucidate their mechanisms of action through an integrated strategy combining chemical profiling, pharmacokinetic screening, network pharmacology, and experimental validation. Methods: UPLC fingerprint and UPLC-QQQ-MS/MS were employed to characterize and quantify the chemical constituents of M. folium. Pharmacokinetic analysis was conducted to identify systemically absorbed compounds. Network pharmacology was applied to predict potential targets and signaling pathways. The lipid-lowering effects were subsequently validated in vitro using an oleic acid/palmitic acid (OA/PA)-induced lipid accumulation model in HepG2 cells and in vivo in a Triton WR-1339-induced hyperlipidemia mouse model. Results: UPLC fingerprint analysis identified 15 common peaks among 21 batches of M. folium, with similarity values ranging from 0.885 to 0.990, indicating good chemical consistency. Eighteen representative compounds were quantified, among which flavone C-glycosides and phenolic acids were predominant. Pharmacokinetic results demonstrated that multiple M. folium’s constituents were absorbed into systemic circulation. Network pharmacology analysis identified 73 potential targets related to hyperlipidemia and highlighted the PI3K-Akt signaling pathway as a key regulatory pathway. In vitro experiments showed that M. folium’s compounds significantly reduced intracellular lipid accumulation and oxidative stress in OA/PA-induced HepG2 cells. Furthermore, in vivo studies demonstrated that vitexin, ferulic acid, isoferulic acid, and N-trans-feruloyltyramine significantly reduced serum and hepatic lipid levels, including TC, TG, and LDL-c, alleviated hepatic steatosis, and improved liver injury and oxidative stress markers in Triton WR-1339-induced hyperlipidemic mice. Conclusions: M. folium exerts significant lipid-lowering effects through multi-component and multi-target mechanisms involving regulation of lipid metabolism and oxidative stress, partly mediated by activation of the PI3K-Akt signaling pathway. These findings provide a scientific basis for the development of M. folium’s natural agents for the treatment of hyperlipidemia. Full article

Replicating the complex physiology of human skin in vitro remains a challenge for cutaneous oncology. Although several three-dimensional (3D) skin and melanoma models have been developed, reproducible skin equivalent systems that enable direct and standardized comparisons between healthy and melanoma-containing skin remain valuable experimental tools. This study aimed to optimize and characterize skin equivalents containing either melanocytes or melanoma cells and to evaluate their utility as platforms for investigating melanoma-associated skin biology and UVB-induced responses in vitro. To achieve this, 3D skin equivalents containing fibroblasts, keratinocytes, and either melanocytes or melanoma cells were reconstructed on a polystyrene scaffold to generate healthy (mc) and melanoma (mm) models. Morphological characteristics were compared with clinically verified human tissue sections, and functional responses to UVB irradiation were assessed with a focus on the kynurenine pathway. The models demonstrated a distinct dermal–epidermal architecture and distinguishable melanoma-associated features, including epidermis-confined melanoma cell clusters, in mm constructs. UVB exposure induced differential responses between models, including significant differences in kynurenine pathway regulation. These findings suggest that the developed skin equivalents provide a reproducible in vitro platform for studying melanoma-associated skin biology and treatment-related metabolic responses and may support future mechanistic studies of skin cancer progression. Full article

Cohen syndrome, caused by pathogenic variants in VPS13B, is characterized by microcephaly, developmental delay, and progressive retinal degeneration, yet the cellular mechanisms linking VPS13B dysfunction to disease pathology remain incompletely understood. Here, we used CRISPR-Cas9 to delete VPS13B exons 2–4 in Phoenix HEK293 cells, generating five independent knockout clones. In all mutant lines, VPS13B disruption caused a marked slowing of cell proliferation due to prolongation of the G1 phase. Immunocytochemistry and transmission electron microscopy revealed that VPS13B mutations causes Golgi apparatus fragmentation, loss of VPS13B Golgi localization, ER lumen dilation with rigid membrane morphology, mitochondrial damage, impaired autophagic maturation, and the appearance of cytoplasmic fibrillary inclusions located close to ER and absent from control cells. RNA-seq analysis identified 27 differentially expressed genes common to all four mutant clones, including downregulation of genes involved in transcriptional regulation, lipid metabolism, and neuronal signaling, alongside upregulation of the stress-response genes CLU and CDKN1A (p21). While our results do not support classical unfolded protein response activation, they are consistent with a model in which lipid bilayer stress and disrupted ER–Golgi trafficking may play a role in the pathophysiology of Cohen syndrome. Together, these findings demonstrate that VPS13B deficiency results in coordinated defects in organelle homeostasis, proteostasis, and cell-cycle progression, providing new dates for understanding Cohen syndrome pathogenesis. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article

Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, yet their polymer-specific effects on endothelial cells remain poorly understood, particularly at the placental and fetal level. We compared cadmium selenide quantum dot-labelled polypropylene (PP) and polyvinyl chloride (PVC) model nanoplastics (NPs) in human umbilical vein endothelial cells (HUVECs) using particle characterization, MTT assays, flow cytometry, confocal microscopy, apoptosis analysis, and synchrotron nano-X-ray fluorescence imaging. PP nanoplastics caused an early reduction in metabolic activity, showed the strongest cell-associated fluorescence, and produced the greatest increase in membrane permeability and late apoptotic/necrotic populations. PVC nanoplastics displayed a more punctate distribution with greater overlap with membrane-associated regions and induced a stronger increase in LC3B-positive vesicular structures. Nano-XRF detected Cd-enriched signals associated with the labelled particles and a polymer-specific Cd–Cl spatial association in PVC-exposed cells. Sulfur mapping further revealed localized sulfur-poor regions along the cell periphery in exposed cells, suggesting localized remodeling of peripheral membranes. These findings indicate that PP and PVC NPs interact differently with endothelial cells and elicit distinct structural and functional responses. Polymer composition should therefore be considered when assessing the vascular and prenatal effects of MNP exposure. Full article

The spread of Bursaphelenchus xylophilus has caused a critical shortage of traditional Poria cocos cultivation materials, making bag-based substrates an urgent alternative. Yet, how substrate stoichiometry shapes nutritional quality remains unclear. Using non-targeted metabolomics combined with redundancy analysis (RDA) and weighted gene co-expression network analysis (WGCNA), we profiled P. cocos cultivated on four substrates: healthy pine logs, pine wilt wood bags, oak bags, and pine needle/branch bags. Bag-cultivated P. cocos showed significantly elevated total amino acids, poria cocos acid, and total triterpenoids, with pine wilt wood bags (P1) performing best overall. Nitrogen, phosphorus, and the N/P ratio independently drove metabolomic variation (pairwise overlap < 5%). Nitrogen-line hub metabolites were negatively correlated with amino acid content, suggesting that suppressed lipid metabolism may free carbon skeletons for the accumulation of nitrogenous nutrients. Phosphorus-line hub metabolites were positively associated with polysaccharide indices, whereas the N/P ratio in line lipid amides showed strong negative correlations with polysaccharides under phosphorus limitation. These correlational patterns are consistent with a stoichiometric resource allocation model, although direct validation through controlled-element experiments is required. These findings provide quantitative guidance for optimizing bag-substrate formulations in P. cocos cultivation. Full article

Fungal nitrogen metabolism is a central determinant of yeast growth, fermentative performance, and secondary metabolism in fungi associated with fermented environments. For Saccharomyces cerevisiae, the assimilation of nitrogen sources found in grape must, including ammonium, free amino acids, and peptides, has been widely characterized, establishing a consumption hierarchy in which proline is considered a non-preferential nitrogenous source. However, the regulation and hierarchy of nitrogen-source utilization in non-conventional fungi remain poorly characterized, particularly in yeasts adapted to anthropized fermentative niches. In this context, Brettanomyces bruxellensis represents a useful fungal model to study the different nitrogen sources that are used, strain-dependent physiology, and survival under nutrient-limited fermentative conditions. We hypothesized that apparent depletion of amino acid and the expression of selected amino acid permease genes are strain-dependent traits linked to the survival of B. bruxellensis. In this study, we evaluated the strain-dependent physiology and amino acid depletion patterns of two B. bruxellensis strains from wine (LAMAP2480 and LAMAP1359). In both cases, the highest apparent depletion values under the 20 amino acid condition were observed for arginine, glutamine, tryptophan and proline, indicating that these compounds contributed substantially to the organic nitrogen pool under the assayed conditions. Only LAMAP2480 isolate was able to grow in the condition without added amino acids, indicating strain and nitrogen source dependence under limited organic nitrogen availability. Transcriptional analysis of GAP1, GNP1, and TAT1 permeases showed expression patterns dependent on both the strain and the available nitrogen source. This is the first study to combine the evaluation of physiological performance, amino acid consumption, apparent nitrogen depletion derived from amino acids normalized to OD₆₀₀ (OD-AA-N depletion), and the transcriptional responses of selected amino acid permease genes. This knowledge may contribute to understanding the survival of B. bruxellensis in fermentation environments with limited nutritional resources. Full article

Citrullus colocynthis (L.) Schrad. (Cucurbitaceae) is a medicinal plant, renowned since antiquity, widely used in traditional medicine for the management of metabolic and inflammatory disorders: seed extracts particularly are reported for the management of rheumatoid arthritis, articular inflammation and skin wound recovery. Our aim was to comparatively evaluate the antioxidant and anti-inflammatory activities of aqueous and oily extracts obtained from mature and immature seeds, and to preliminarily assess their dermal tolerance and protective effects against induced inflammation and UV damage. Antioxidant activity was investigated in vitro using β-carotene bleaching and ferric reducing antioxidant power (FRAP) assays, whereas anti-inflammatory activity and anti-irritation effects were evaluated in vivo in a mouse model using the xylene-induced ear edema and the UV-induced skin irritation test. Oily extracts from both maturation stages showed marked inhibition of β-carotene oxidation, while the aqueous extract of immature seeds exhibited the highest ferric reducing capacity; on the other hand, fixed oils demonstrated a significantly greater inhibitory effect on oedema, suggesting a higher efficacy in modulating acute inflammatory responses. Results showed how C. colocynthis seed maturity and extraction solvent influence the bioactive potential of these ingredients for phytotherapeutic and dermo-functional applications, supporting a possible use against wrinkle formation and UV-induced skin alterations. Full article

Metformin is a widely prescribed antidiabetic agent with pleiotropic effects extending beyond glycemic control, including anti-inflammatory and antioxidant actions. However, its impact on cytokine signaling and ferroptosis-related pathways in brown adipose tissue (BAT) remains poorly characterized. Here, we examined the transcriptional and metabolic responses to metformin in brown adipocytes and in a diet-induced obesity model. Differentiated brown adipocytes were treated with metformin and analyzed by RNA sequencing and RT-qPCR. C57BL/6 male mice fed a high-fat diet (HFD) were administered metformin to assess systemic metabolic parameters and BAT-specific responses, with validation by histology, RT-qPCR, and Western blot. Transcriptomic profiling identified differentially expressed genes enriched in cytokine–cytokine receptor interaction and ferroptosis-related KEGG pathways. Metformin modulated the expression of multiple inflammatory cytokine genes and upregulated antioxidant and ferroptosis defense-related genes, including the glutathione biosynthesis genes Gclc and Gclm, together with Hmox1, Gpx4, Nfe2l2 (Nrf2), and Slc7a11. Among these, Gpx4 showed the most consistent upregulation across mRNA and protein levels in BAT. In HFD-fed mice, metformin improved glucose tolerance and elevated the expression of antioxidant and ferroptosis-related genes in BAT, consistent with the in vitro findings. Together, these results indicate that metformin coordinately modulates antioxidant and ferroptosis defense-related gene expression in BAT, suggesting a tissue-protective transcriptional program under metabolic stress. Our findings identify candidate immunometabolic and ferroptosis-related targets of metformin in BAT and provide a basis for further mechanistic investigation of its tissue-specific actions beyond glycemic control. Full article

Early identification of individuals with abnormal glucose metabolism is essential for timely intervention and prevention of diabetes-related complications. Routine laboratory testing generates large amounts of clinical data that may support automated glycemic classification through machine learning approaches. This study aimed to develop and evaluate a machine learning framework for the classification of HbA1c-defined glycemic status using routinely available clinical laboratory features. A retrospective dataset of 1434 individuals with available glycemic measurements was analyzed. Participants were categorized into HbA1c-defined normoglycemic, prediabetic-range, or diabetic-range groups. Three concurrent classification tasks were examined: HbA1c-defined dysglycemia classification, diabetic-range HbA1c classification, and multiclass HbA1c-defined glycemic-status classification. Demographic, biochemical, and hematological variables were used as predictors. Data preprocessing included missing-value handling, feature filtering, and outlier treatment. Several supervised learning algorithms were evaluated, including Logistic Regression, Random Forest, Gradient Boosting, Support Vector Machine, and Multinomial Logistic Regression. Model performance was assessed using train–test validation and cross-validation with accuracy, precision, recall, F1-score, and area under the receiver operating characteristic curve. For dysglycemia, Gradient Boosting achieved the highest AUC (0.848), while Random Forest achieved the highest accuracy (0.801) and sensitivity (0.908). For diabetic-range HbA1c, Random Forest achieved the highest AUC (0.864), whereas SVM achieved the highest accuracy (0.794). In multiclass classification, Random Forest achieved the highest accuracy (0.610), while Gradient Boosting achieved the highest macro-AUC (0.796) and macro-F1 score (0.603). Pairwise comparisons showed no statistically significant superiority of any classifier after Holm correction. Clinical-baseline and ablation analyses demonstrated that fasting glucose accounted for a substantial proportion of discrimination, with only modest incremental value from additional laboratory variables. These findings support cautious interpretation of routine laboratory-based classification models pending further validation and clinical-utility assessment. Full article

Evaluating the in vivo systemic tolerance of phytogenic feed additives is a crucial prerequisite before their widespread application in vulnerable newborn ruminants. This study aimed to investigate the systemic effects of orally administered cold-pressed Nigella sativa oil on the hematological and biochemical profiles of neonatal lambs (0–45 days of age) fed exclusively on colostrum and maternal milk. The pre-specified primary endpoint was the absence of clinically meaningful change in hepatorenal markers and complete blood count between groups over 45 days. Thirty-two single-born Merino lambs were divided into a treatment group that received 1.5 mL/day of the oil for the first 15 days of life and an untreated control group. Blood samples were collected on days 0, 7, 21, and 45 to evaluate both immediate and carry-over physiological effects. Using a covariate-adjusted linear mixed-effects model to account for baseline variances, the results demonstrated that the oil was physiologically well-tolerated. The supplementation exerted no significant adverse effects (p > 0.05) on hepatorenal markers or the measured acute-phase protein. The supplementation maintained neonatal energy metabolism stability without inducing artificial lipid suppression in serum triglycerides or total cholesterol levels. Furthermore, the oil preserved hematological homeostasis without negatively impacting red blood cell indices and modulated platelet distribution width indices without causing pathological thrombocytosis. In conclusion, the early direct oral administration of N. sativa oil is a physiologically well-tolerated supplement that supports basal metabolic and hematological stability in pre-ruminant lambs without inducing systemic disruptions within the parameters measured. Full article

Twenty-five years after our identification of the genetic defect in GNE Myopathy (GNEM), we review the current state-of-affairs in the research of this unique myopathy. In this narrative review, we describe the clinical aspects of this myopathy, the genetics of this muscle disorder, the biochemistry of the GNE enzyme, and the animal models that have been developed. We critically discuss the accumulating scientific and clinical data that show that hyposialylation cannot be the sole explanation for the disease pathomechanism. The negative or minimal effects of sialic acid supplementation in clinical therapy trials of GNEM call for a re-evaluation of future planned trials. We review the known facts and the current enigmas as well as research controversies in this field. We also discuss the prospects for further basic research, as a reliable animal model of GNEM is lacking, and future genetic therapy of this myopathy. Full article

The integration of digital therapeutics (DTx), wearable electronic devices, and artificial intelligence (AI) represents a significant advancement in personalized healthcare. The primary purpose of this structured narrative review is to evaluate the convergence of these technologies, providing a consolidated framework that bridges the gap between raw biometric data acquisition and actionable, AI-driven clinical insights. This paper synthesizes the latest literature on the intersection of mobile health (mHealth), machine learning (ML), and physiological tracking, with a primary focus on heart rate variability (HRV) and associated biochemical markers, such as cortisol, salivary alpha-amylase, and interleukins. Instead of viewing wearable outputs simply as raw data, we critically evaluate the technical verification and clinical validation required to define them as true “digital biomarkers.” By evaluating multimodal sensor technologies and advanced predictive algorithms, this paper outlines the clinical utility of digital biomarkers in diagnosing and proactively managing cardiovascular, neurological, metabolic, and psychiatric conditions, noting classification accuracies frequently exceeding 85% in controlled settings. However, we strongly caution that internally validated performance in controlled settings does not inherently demonstrate external clinical utility. The clinical relevance of this study lies in its holistic approach to identifying how continuous monitoring can broaden healthcare accessibility while improving precision medicine. Furthermore, it deeply addresses the technical challenges of highly variable ambulatory data quality, the necessity for robust artifact reduction (e.g., via LSTM and GAN architectures), and the limitations of small, homogeneous training datasets. We highlight the essential need for demographic-aware algorithmic models, external validation, and decentralized privacy-preserving models (e.g., federated learning) in diverse populations to ensure the safe, equitable clinical translation of DTx, mHealth, ML, and AI technologies. Full article