Search Results (5,875)

Nitrogen is a critical macronutrient for plants, playing a central role in the synthesis of proteins, amino acids, and nucleic acids. To enhance nitrogen use efficiency (NUE) and ensure sustainable agricultural production, identification of nitrogen-efficient genes and application of molecular breeding techniques are crucial for developing high-NUE rice germplasm. The nitrogen signaling pathway exhibits close crosstalk with phytohormones, including auxins (IAA), gibberellins (GAs), abscisic acid (ABA), cytokinins (CTKs), brassinosteroids (BRs), and strigolactones (SLs). This review systematically summarizes the molecular mechanisms underlying crosstalk between nitrogen and phytohormones, focusing on the physiological and molecular basis underlying their synergistic regulation of root development and NUE in rice, and outlines challenges for the complicated research field and prospective directions in future. Full article

Plants in agricultural systems rarely face single stressors; instead, they encounter concurrent biotic (pathogen, pests) and abiotic (drought, salinity, heavy metals) stresses that causes severely reduce crop yields and endanger food security. The traditional methods of breeding, genetic engineering, and agrochemicals tend to target individual stresses and still do not suffice in the complex field conditions. Compared to these approaches, nanotechnology offers distinct advantages: nanoparticles (NPs) can be applied as foliar sprays or seed treatments without lengthy breeding cycles or regulatory hurdles associated with genetically modified organisms. However, nanotechnology is not inherently “better” but rather complementary to crop engineering; each approach has specific strengths. Breeding and genetic engineering provide heritable, long-term solutions, while nanotechnology offers immediate, season-specific, and reversible interventions. Cross-tolerance, the phenomenon whereby exposure to one stress enhances tolerance to another, offers a promising alternative. This review critically examines how NPs act as stress-priming agents that induce cross-tolerance by activating overlapping defense networks, including antioxidant systems (SOD, CAT, APX), phytohormonal crosstalk (ABA, SA, JA), osmolyte homeostasis, and stress-responsive gene expression. We synthesize current evidence on NP uptake, translocation, and cellular interactions, and evaluate their dual role in directly suppressing pathogens while simultaneously enhancing plant immune responses and physiological resilience. However, efficacy is highly dose-dependent: low, subtoxic doses prime defense through hermetic ROS signaling, whereas supraoptimal doses cause phytotoxicity. The current challenges in nano-mediated stress alleviation include: (i) a persistent laboratory-to-field translation gap, with field outcomes averaging only 60–70% of greenhouse efficacy; (ii) dose-dependent phytotoxicity; (iii) poor reproducibility across studies; (iv) scalability and formulation stability issues; and (v) insufficient understanding of long-term environmental fate, including soil accumulation, non-target organism effects, and food chain safety. Future research should consider field-validated formulations (e.g., SiNPs, ZnONPs, Fe₃O₄NPs) across major staple crops); integrating nanotechnology with precision agriculture through nanosensors, remote sensing, and artificial intelligence for site-specific, dose-optimized applications;developing smart, biodegradable nanoparticles with stimuli-responsive release; and establishing harmonized regulatory frameworks for nano-agrochemical approval. When deployed responsibly, nanoparticle-induced cross-tolerance represents a sustainable approach to improve crop resistance against multifactorial stress, with significant implications for climate-resilient agriculture and global food security. Full article

Prevalent cancers primarily include breast, lung and bronchus, prostate, and colorectal cancers. In contrast, cancer of the epididymis is very rare, and we propose that this tissue could carry inherent anticancer components, in particular, small extracellular vesicles (EVs) with antineoplastic properties. All cell types release extracellular vesicles (EVs) into their intercellular space, which act in the crosstalk required to achieve homeostasis. Among these, small EVs, which are membrane-bound vesicles with an average diameter of 30–200 nm, can transfer cell-specific cargo, such as lipids, proteins, DNA and RNA, which can be selectively received by neighboring or distant cells, and trigger specific cell processes, such as growth, division, or apoptosis. Here, we isolated small EVs from epididymis tissue, and examined their effect on morphology, viability, apoptosis, cell cycle phases, and certain gene and protein expression levels, particularly of the pro-apoptotic p53 protein, in HCC38 and MCF-7 breast cancer cell lines, as well as in a normal fibroblast cell line. The various analyses demonstrated effects on breast cancer cells but not on normal cells. Specifically, epididymis-derived EVs (Ep-EVs) selectively induced apoptosis and cell cycle arrest in cancer cells, while normal cells were unaffected. Moreover, the relative uptake of Ep-EVs in HCC38 and MCF-7 breast cancer cells was significant, indicating a direct association between vesicle internalization and the biological response. Taken together, these findings demonstrate a solid experimental foundation supporting the therapeutic potential of Ep-EVs in breast cancer, with promising implications for their development as a broader anticancer platform. Full article

Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease affecting the axial skeleton, characterized by progressive structural damage and functional impairment. Although biologic therapies targeting tumor necrosis factor and interleukin-17 have improved clinical outcomes, a substantial proportion of patients fail to achieve sustained disease control. Emerging evidence suggests that metabolic alterations may contribute to AS pathogenesis; however, systematic characterization of metabolism-related biomarkers and their regulatory networks remains limited, and the interplay between metabolic dysfunction and immune dysregulation in AS is poorly understood. Two whole-blood GEO datasets (GSE25101, GSE73754; n = 104) were integrated as the primary analytical cohort. A third dataset (GSE11886, n = 18; monocyte-derived macrophages) was included for exploratory cross-tissue analysis. Differential expression analysis identified 847 DEGs, which were refined to 16 metabolism-related genes through weighted gene co-expression network analysis (WGCNA) and GeneCards database filtering. Eleven machine learning algorithms with 5-fold cross-validation were applied to construct diagnostic models and identify hub genes. Validation analyses included immune cell infiltration estimation using CIBERSORT, metabolic pathway activity assessment via ssGSEA, single-cell transcriptomics from GSE268839, functional enrichment through GSEA/GSVA, and chromosomal localization analysis. A competing endogenous RNA (ceRNA) regulatory network was constructed to map post-transcriptional regulation. Natural compounds from 66 AS-treating traditional Chinese medicines were screened against hub genes using deep learning-based binding prediction. Multiple machine learning algorithms achieved comparable cross-validated performance (CV AUC range 0.741–0.836; top five models: 0.805–0.836) using the six hub genes (MFN2, SLC27A3, RHOB, SMG7, AKR1B1, LCOR) identified through SHAP-based feature importance analysis of the PLS model. Leave-one-dataset-out validation between the two whole-blood cohorts showed that all algorithms exceeded an AUC of 0.77 in Round 1 (validate: GSE73754, n = 72; best AUC 0.861), while Round 2 (validate: GSE25101, n = 32) yielded more modest performance (best AUC, 0.715) reflecting the smaller validation sample. Exploratory application to GSE11886 (macrophage-derived samples) showed near-chance performance, consistent with the tissue-source discrepancy. AS patients exhibited significant downregulation of oxidative phosphorylation, TCA cycle, and glycolysis pathways (p < 0.01), accompanied by elevated glutathione metabolism (p < 0.001). Immune cell deconvolution revealed reduced CD8+ T cell proportions correlating with MFN2 downregulation, and increased neutrophil frequencies correlating with SLC27A3 upregulation. Exploratory single-cell analysis indicated that RHOB expression was relatively enriched in border-associated macrophages and fibroblasts, while AKR1B1 was more prominently expressed in vascular endothelial cells and plasmacytoid dendritic cells. The ceRNA network identified 21 miRNAs and 65 lncRNAs forming 86 regulatory interactions, with four key regulatory axes (SATB1-AS1/miR-539-5p/LCOR, FAM95B1/miR-223-3p/RHOB, LINC01106/miR-106a-5p/MFN2, AATBC/miR-185-5p/SMG7) predicted to regulate hub gene expression. Compound screening identified betaine, pyruvic acid, citric acid, etc., as top-ranking candidates, with MFN2 showing the highest binding capacity among hub genes. This study provides an integrative framework linking metabolic reprogramming with immune dysfunction in AS. The six-gene diagnostic signature showed preliminary discriminatory ability in the available datasets, while the ceRNA regulatory network and natural compound screening results prioritize candidate regulatory pathways and compounds for future validation. These findings advance our understanding of AS pathogenesis and may guide future biomarker development and targeted intervention strategies. Full article

Peripheral T-cell lymphomas (PTCLs) are malignancies of mature T cells with a poor prognosis. Most PTCL cases express follicular T-helper (T_FH) cell antigens and are classified as T_FH cell lymphoma (TFHL). Contact-dependent signaling between CD40 and its ligand, CD154, is essential for immune functions. CD154 is expressed by activated T cells, while CD40 is found on B cells, follicular and other dendritic cells, macrophages, and stromal cells. Although the CD40–CD154 crosstalk is a key costimulatory pathway in immune responses, data on its role in PTCLs are limited. To explore the role of the CD40–CD154 axis in TFHLs, we conducted an in-depth immunomorphological study of 111 PTCL cases, including 93 TFHL cases. We found that neoplastic T cells in TFHL are consistently CD154-positive. The CD154 expression increased in histologically advanced cases and correlated with the extent of CD40 positivity. We showed that CD154-positive neoplastic T cells recapitulate the intranodal migration of normal TFH cells, disrupting and remodeling each functional compartment, thereby explaining the disease-related immune dysfunction. Our findings indicate that pathological CD40–CD154 interaction is a potential driver mechanism in TFHL and offers a promising target for future therapies. Full article

Osmotic stress limits rice productivity, yet the crosstalk between hydrogen sulfide signaling and redox regulation remains incompletely understood. We previously showed that redox-dependent oligomerization of the basic (region) leucine zippers transcription factor bZIP68 at Cys245 confers osmotic tolerance. However, the role of an adjacent cysteine, Cys171, was undefined. Here, we demonstrate that osmotic stress induces persulfidation of bZIP68 specifically at Cys171. This modification facilitates Cys245-mediated oxidation-dependent oligomerization, thereby enhancing bZIP68 transcriptional activity toward COLD-REGULATED413-THYLAKOID MEMBRANE1 (COR413-TM1). Transgenic complementation and physiological assays confirmed that Cys171 persulfidation is essential for full bZIP68 function in osmotic adaptation. Transcriptomic analysis further revealed that Cys171 is required for bZIP68-driven transcriptional reprogramming under stress. Our findings establish a hierarchical redox cascade wherein persulfidation primes bZIP68 for oxidative activation, highlighting a regulatory crosstalk between distinct post-translational modifications. These mechanistic insights expand our understanding of H₂S signaling and identify the bZIP68 cysteine network as a potential target for improving crop stress resilience. Full article

Cardiac fibrosis is a central determinant of heart failure progression and arises from pathological remodeling characterized by fibroblast activation, myofibroblast differentiation, and excessive extracellular matrix deposition. In contrast, physiological remodeling permits adaptive cardiac growth without net fibrosis. Pregnancy represents an underexplored physiological model of reversible cardiac remodeling. In response to hemodynamic load, the maternal heart undergoes hypertrophic growth that resolves postpartum, constituting a natural paradigm of fibrosis-resistant cardiac adaptation. Pregnancy and lactation are accompanied by profound endocrine and immune reprogramming of maternal tissues. We propose that this hormonal milieu orchestrates coordinated crosstalk among endothelial cells, fibroblasts, and immune cell populations to suppress profibrotic pathways and preserve extracellular matrix homeostasis. Candidate regulators include estrogen, progesterone, prolactin family peptides, relaxin, oxytocin, and components of the renin–angiotensin–aldosterone system. During the postpartum and lactational period, prolactin and oxytocin may further promote reverse remodeling. These hormones likely act by modulating local cytokine and growth factor networks that otherwise drive fibroblast activation. By focusing on non-myocyte cardiac cells and extracellular matrix dynamics, this review positions pregnancy as a translational model to uncover endogenous anti-fibrotic mechanisms and identify novel therapeutic strategies for cardiac fibrosis. Full article

The redox mechanisms of RAW 264.7 macrophages exposed to 2.45 GHz RF-EMF at subthermal specific absorption rates and to lipopolysaccharide (LPS) and/or the SARS-CoV-2 spike protein (CSP) were investigated. To this end, cellular responses (lysosomal and mitochondrial activity, nitric oxide (NO) production, and cell survival/death) were measured after 6, 24, and 48 h. Selective loss of viability in cells exposed to RF and LPS was observed at 6 h, consistent with early defects in membrane permeability. Lysosomal activity was significantly enhanced in cells treated with RF + LPS. Mitochondrial activity decreased in cells exposed to RF + LPS at 6 h and increased in cells treated with RF + CPS/LPS. Cell viability decreased greatly in cells treated with LPS and CSP + LPS after 24, particularly after 48 h. Nitrite levels peaked in non-irradiated cells treated with RF + LPS and in CSP + LPS at 24 h and decreased in irradiated cells after 48 h. Irradiation affected selection of the death mode: apoptosis decreased or remained unchanged in cells subjected to any of the treatments, while necrosis increased in cells treated with CPS, LPS, or both for 48 h. The combination of RF-EMF and infectious agents reprogrammed the interaction between mitochondria/lysosomes/nitric oxide (NO)/cell death in macrophages in a time- and stimulus-dependent manner. Full article

Background/Objectives: Zebrafish fin regeneration serves as a classic model for investigating vertebrate tissue regeneration, yet the core regulatory networks and their crosstalk with the immune microenvironment remain incompletely characterized. This study aimed to identify hub genes, and elucidate the underlying molecular mechanisms and immune microenvironment dynamics during zebrafish fin regeneration. Methods: We integrated multiple bulk RNA-seq datasets of zebrafish fin regeneration from the GEO database, followed by data standardization with batch effect removal. Hub genes were screened via differential expression analysis, weighted gene co-expression network analysis (WGCNA), and predictive models constructed with 13 classic machine learning algorithms. Functional enrichment, time-ordered gene co-expression network (TO-GCN) method, immune infiltration analyses and RT-qPCR validation were further performed. Results: We identified upregulated differentially expressed genes, regeneration-correlated gene modules and their overlapping genes, including 82 candidate genes and 10 hub genes enriched in cytoskeleton remodeling, extracellular matrix organization, and focal adhesion. Temporal analysis uncovered hierarchical gene regulation and functional switching during regeneration. Hub gene expression was significantly correlated with the infiltration of B cells, M1/M2 macrophages and CD8+ T cells, revealing a stage-specific immune microenvironment. RT-qPCR validation showed high consistency with the multi-omics data. Conclusions: This study provides potential gene targets for understanding zebrafish fin regeneration, and offers a valuable reference for investigating the crosstalk between regulatory networks and the immune microenvironment in vertebrate tissue regeneration. Full article

Cardiac surgery represents a cornerstone of modern cardiovascular medicine, yet it is intrinsically linked to significant systemic stress responses that can compromise remote organ function. Among postoperative complications, cardiac surgery-associated acute kidney injury (CSA-AKI) remains a significant clinical challenge characterized by high morbidity and complex pathophysiology. While hemodynamic instability and ischemia–reperfusion injury are established risk factors, renal dysfunction frequently persists despite optimal perfusion. This observation suggests the involvement of potent circulating mediators in cellular injury. Extracellular vesicles (EVs) are essential for intercellular communication and serve as central hubs for transporting bioactive lipids, proteins, and genetic material. Accumulating evidence indicates that the mechanical and oxidative stress inherent to cardiopulmonary bypass triggers substantial release of EVs from platelets, erythrocytes, and injured vascular tissues. These vesicles may function as vectors that traffic oxidized mitochondrial components and pro-inflammatory cargo to the renal parenchyma. This signaling cascade appears to disrupt renal homeostasis through a proposed “dual-hit” mechanism involving the induction of endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT), followed by tubular epithelial injury via mitochondrial fragmentation, redox imbalance, and downregulation of anti-aging factors. The complexity of these EV-mediated interactions may contribute to an incomplete understanding of why specific patient phenotypes fail to recover. This narrative review examines the mechanisms of surgery-induced EV biogenesis, the molecular pathogenesis of endothelial and tubular damage, and the role of intercellular crosstalk. Additionally, we discuss future perspectives on targeting the “EV vector” through therapeutic apheresis and mitochondrial pharmacotherapy to potentially improve clinical outcomes in high-risk surgical patients. Full article

Myocardial infarction (MI) triggers a robust inflammatory response that is essential for tissue repair but, when excessive or prolonged, drives pathological cardiac remodelling and heart failure. Colony-stimulating factor 2 (CSF2) signalling has been implicated in driving pro-inflammatory macrophage activation post-MI. Here, we investigated the role of macrophage-specific CSF2 receptor alpha (CSF2RA) signalling in post-MI remodelling using a tamoxifen-inducible genetic mouse model and permanent coronary artery ligation. Macrophage-specific Csf2ra deficiency significantly improved left ventricular systolic function post-MI without altering cardiac fibrosis burden. Functional improvement was associated with enhanced collagen scar maturation, characterised by an increased proportion of mature collagen fibres, and with accumulation of anti-inflammatory, pro-reparative macrophages within the infarct. These macrophage changes were accompanied by increased fibroblast density, consistent with altered macrophage–fibroblast crosstalk. Collectively, these findings identify macrophage-intrinsic CSF2RA signalling as a critical regulator of inflammatory resolution and scar maturation after MI and provide mechanistic support for the rationale of selective CSF2RA inhibition as a therapeutic strategy to limit adverse cardiac remodelling and improve post-infarction recovery. Full article

Lentils (Lens culinaris; family: Fabaceae) are increasingly recognized as functional legumes with potential benefits for gut health because they provide bioactive peptides, resistant starch, and polyphenol-rich fractions within a shared food matrix. However, most existing studies have focused on individual lentil-derived compounds, and their matrix-dependent complementary interactions during digestion and fermentation remain insufficiently resolved. This review synthesizes current evidence on lentil-derived peptides, resistant starch, and polyphenols, with particular emphasis on their matrix-dependent complementary relationships, digestion-dependent transformation, microbial co-metabolism, and implications for intestinal barrier function. During gastrointestinal digestion and colonic fermentation, lentil proteins, resistant starch, and phenolic compounds undergo sequential transformation, yielding bioactive peptides, fermentable substrates, short-chain fatty acids (SCFAs), and phenolic metabolites that may collectively influence microbial composition and metabolic activity. Emerging evidence suggests that these interconnected processes may support gut health through microbiota–host crosstalk by modulating tight junction-related markers, reducing intestinal permeability, and maintaining epithelial homeostasis. Mechanistically, these effects have been associated with SCFA-mediated G protein-coupled receptor (GPCR) signaling, suppression of TLR4–NF-κB/MAPK inflammatory cascades, and activation of Keap1–Nrf2 antioxidant defenses, thereby attenuating oxidative stress and pro-inflammatory responses. Current evidence is more consistent with matrix-dependent complementary or convergent actions than with demonstrated synergy. At present, phenolic-rich fractions provide clear pathway-level evidence, whereas fermentation-linked carbohydrate effects are more strongly supported by microbiota- and in vivo-associated outcomes, and protein- or peptide-related mechanisms remain comparatively underdefined. Nevertheless, the evidence base remains limited by the scarcity of integrated studies, well-controlled human intervention trials, and factorial experimental designs capable of distinguishing complementary, additive, and truly synergistic effects among lentil bioactives. This review therefore highlights the need to move from describing coexisting beneficial effects toward formally testing interaction effects within physiologically relevant lentil matrices. Full article

Ethanol exposure causes microbial imbalance, damages the gut barrier, and increases oxidative stress along the gut–liver axis, leading to the development and progression of alcohol-associated liver disease (ALD). Arginine is a conditionally essential amino acid that may play a key role in maintaining redox homeostasis and mediating host–microbiota crosstalk. We hypothesized that supplemental arginine provided during chronic ethanol exposure in mice would mitigate oxidative damage via the gut–liver axis. Our findings suggest that arginine supplementation mediated hepatic steatosis, preserved body weight and fat, and reduced oxidative stress in the gut–liver axis. These changes were associated with alterations in gut microbiota composition and function. These data support a potential role for arginine supplementation in mitigating ethanol-induced oxidative damage via the gut–liver axis. Full article

Obesity is recognized as a risk factor for breast cancer development and progression. Adipocytes exert their oncogenic effects through complex and interconnected biological mechanisms that encompass metabolic dysfunction, chronic low-grade inflammation, and systemic endocrine alterations. Herein, we reviewed the current evidence explaining how obesity induces a state that reprograms adipose tissue and remodels the breast cancer tumor microenvironment (TME). We first discuss the systemic and local mechanisms linking obesity to inflammation and how these alterations reshape the functional organization of the mammary gland. Then, we discuss how the chronic exposure to tumor-derived signals, together with the altered metabolic state of obese adipose tissue, induces a functional reprogramming of adipocytes, giving rise to so-called cancer-associated adipocytes (CAAs), which actively contribute to tumor progression. Also, the strengths and limitations of biological models to study the crosstalk between adipocytes and tumor cells, including two-dimensional (2D) monolayers and three-dimensional (3D) cell cultures, as well as animal models, are discussed. Special emphasis is placed on 3D co-culture models, which more accurately reproduce spatial organization, direct cell–cell contact, and diffusion dynamics, providing a more physiologically relevant environment for studying how obesity and inflammation reshape the TME in breast cancer. Finally, we highlight the limitations of conventional experimental models and review recent advances in 3D-based platforms, emphasizing their mechanistic insights and translational potential. Full article

Oxidative stress and gut microbiota dysbiosis establish a self-perpetuating loop that disrupts epithelial barrier integrity and fuels chronic inflammatory and metabolic disorders, including inflammatory bowel disease (IBD), metabolic syndrome (MS), and chronic kidney disease (CKD). This systematic review synthesizes mechanistic, preclinical, and clinical evidence linking reactive oxygen species (ROS), microbiota-derived metabolites, and host redox homeostasis, with a focus on probiotic-based interventions. Comprehensive searches of PubMed, Scopus, Web of Science, and Google Scholar (2000–March 2026) identified in vitro, animal, and human studies, as well as systematic reviews and meta-analyses, assessing oxidative biomarkers, microbiome profiles, and barrier function outcomes. Probiotic strains, predominantly Lactiplantibacillus, Bifidobacterium, and emerging next-generation taxa, attenuate oxidative stress by inducing antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx)], activating Nrf2 signaling, and restoring short-chain fatty acid (SCFAs) production, thereby lowering malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) while enhancing total antioxidant capacity (TAC). At the mucosal interface, probiotics strengthen tight junction proteins, suppress NF-κB-mediated cytokine release, and mitigate dysbiosis, contributing to clinically meaningful improvements in disease activity, insulin sensitivity, and uremic toxin burden along gut–liver, gut–kidney, and other gut–organ axes. Overall, current evidence supports probiotics and synbiotics as promising adjuncts for nutrition-driven redox modulation, while highlighting the need for strain-resolved, multi-omics, multicenter trials with standardized redox and microbiome endpoints to optimize dosing strategies and long-term safety. Full article