Search Results (10,836)

Mediator is a central transcriptional coactivator that connects sequence-specific transcription factors with RNA polymerase II to control inducible gene expression in plants. MED16 is a Mediator tail module subunit that functions as a context-dependent integrator, helping coordinate developmental programs with environmental adaptation. This review summarizes current evidence for MED16 function from structural and evolutionary perspectives to physiological outputs, with emphasis on how MED16 interacts with transcription factors and other Mediator subunits to shape RNA polymerase II engagement at target loci. In terms of development, MED16 contributes to organ growth and root system architecture, and comparative studies have revealed that it plays conserved roles in lineage-specific wiring. Under abiotic stress, MED16 supports the efficient activation of stress-inducible transcription, including cold acclimation and nutrient stress responses such as phosphate starvation-dependent root remodeling. In immunity, MED16 modulates salicylic acid- and jasmonate/ethylene-associated defence outputs and can be targeted by plant viruses, which is consistent with its role in antiviral transcriptional responses. Mechanistically, MED16 participates in cooperative and competitive interactions within the Mediator complex that tune hormone-responsive outputs, exemplified by MED25-related competition in abscisic acid signalling. We highlight key limitations and future directions, including the need for mechanistic validation beyond Arabidopsis, clearer models of dosage control in crops, improved understanding of context-dependent tail configurations, and high-resolution mapping of MED16 interaction interfaces. Full article

Glioblastoma stem cells (GSCs) function as dynamic regulators of tumor persistence, maintained by interconnected genetic, epigenetic, metabolic, and microenvironment-derived circuits. Rather than fixed entities, GSCs continuously recalibrate their functional state as transcriptional regulators, chromatin architecture, and non-coding RNA networks shift in response to microenvironmental cues. Hypoxic, vascular, and immune niches reinforce these adaptive states by stabilizing HIF signaling, modulating cytokine gradients, and sustaining immunosuppression. Metabolic flexibility further supports survival under therapeutic and environmental stress. Standard therapies inadvertently activate these same resilience pathways: TMZ enhances DNA repair and quiescent survival, while radiation promotes mesenchymal transition and immune evasion, thereby enriching GSC-associated circuits that drive recurrence. Understanding how these molecular circuits converge to sustain stemness, plasticity, and microenvironmental crosstalk highlights the need for combinatorial strategies that simultaneously disrupt epigenetic gating, metabolic rewiring, ncRNA-controlled repair, and niche-dependent signaling to achieve durable glioblastoma control. Full article

Exercise-induced muscle damage (EIMD) has classically been attributed to localized mechanical disruption following eccentric contractions. Emerging evidence, however, indicates that EIMD represents a systems-level failure of stress integration within skeletal muscle rather than a purely mechanical lesion. Mechanical loading initiates disturbances in intracellular Ca²⁺ homeostasis, which interact with metabolic stress, redox imbalance, and immune activation to form self-reinforcing feedback loops. When compensatory capacity is exceeded, transient injury may shift toward maladaptive remodeling marked by mitochondrial dysfunction, ferroptosis, chronic inflammation, and impaired regeneration. Recent studies identify reactive oxygen species accumulation, iron-dependent lipid peroxidation, dysregulated energy sensing, and aberrant immune polarization as key molecular tipping points governing injury reversibility. Beyond their regenerative role, satellite cells act as integrators of metabolic history and epigenetic memory, linking repetitive injury to reduced muscle adaptability, age-related sarcopenia, and heightened metabolic disease risk. Here, we synthesize evidence from animal models, clinical studies, and multi-omics analyses to establish a systems biology framework for EIMD. We delineate the spatiotemporal interactions among mechanical, metabolic, oxidative, immune, and regenerative modules; identify regulatory nodes that determine adaptive repair versus pathological outcomes; and critically evaluate current nutritional, physical, pharmacological, and regenerative interventions from a mechanism-oriented perspective. Finally, we discuss how multi-omics, digital monitoring, and individualized rehabilitation may enable precision management of EIMD and advance understanding of muscle stress resilience and adaptive limits. Full article

Etrasimod is an oral selective sphingosine-1 phosphate receptor modulator, and its anti-inflammatory mechanism of action in inflammatory bowel diseases is not completely understood. It targets pro-inflammatory immune cells expressing sphingosine-1-phosphate receptors during their migration from the lymphatic system to the circulation and intestinal mucosa. Reductions in certain lymphocyte subsets in the peripheral blood have been reported, but its effects in lymph nodes remain unknown. This study investigated changes in leukocyte subpopulations in peripheral lymph nodes and blood in Crohn’s disease patients treated with etrasimod. Moderate-to-severe Crohn’s disease patients participated in this randomized, double-blind study, within the phase 2 CULTIVATE clinical trial. At baseline and after 14 weeks of etrasimod treatment, peripheral blood and inguinal lymph node biopsies were obtained. Isolated peripheral blood mononuclear cells and lymph node leukocyte populations were analyzed at single cell level using mass cytometry at both timepoints. The immunophenotyping revealed 15 innate and adaptive major immune cell populations, as well as 14 subpopulations of CD4+ and CD8+ T-cells. In peripheral lymph nodes, etrasimod resulted in significant accumulation of naïve, central memory, and effector memory CD4+ T-cells (+10.7%, +4.2%, and +2.3%, respectively; all p = 0.03), as well as naïve CD8+ T-cells (+4.2%; p = 0.03). Conversely, these subsets were reduced in peripheral blood (−6.2%, −6.0%, −2.0%, and −2.2%, respectively; all p = 0.03). Naïve and memory B-cells decreased in the circulation (−1.7%, p = 0.057; −0.6%, p = 0.03, respectively) but were unchanged in the lymph nodes. Innate immune cell populations remained mostly unaffected in both compartments. Our data indicate that etrasimod’s pharmacodynamic effect is related primarily with the attenuation of the T-cell mediated inflammation with minor changes in B-cells. However, additional follow-up studies are needed for the validation of these observations in the context of Crohn’s disease. Full article

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically ‘cold’ tumors into ‘hot’ ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects of the double recombinant vaccinia virus VV-GMCSF-Lact, which carries the human GM-CSF gene, with those of recombinant human GM-CSF (rhGM-CSF) in an immunocompetent murine GL261 glioma model. Methods: The study was conducted using a subcutaneous GL261 glioma model in immunocompetent C57BL/6 mice, comparing intratumoral VV-GMCSF-Lact and rhGM-CSF treatments with evaluation of immune cell populations by flow cytometry, tumor morphology by H&E staining, and tumor transcriptome profiles by RNA sequencing. Results: Flow cytometry showed that VV-GMCSF-Lact reduced the number of immunosuppressive cells in the TME of subcutaneously transplanted gliomas, targeting different components of the TME depending on animal sex. The immunotherapeutic effects of rhGM-CSF were less pronounced and primarily affected peripheral immune cells. Histological analysis revealed a decrease in mitotic figures in tumors from female mice after viral therapy. Transcriptome profiling of GL261 tumors demonstrated divergent gene expression patterns and cellular compositions between treatment groups. VV-GMCSF-Lact treatment was associated with a decreased proportion of malignant GL261 cells and CD8⁺ T lymphocytes, while rhGM-CSF treatment increased proportions of MDSCs, macrophages, NK cells, and tumor-associated neutrophils. Conclusions: Taken together, our data demonstrate that VV-GMCSF-Lact induces antitumor immune responses in murine GL261 glioma in vivo and modulates the tumor microenvironment more effectively than rhGM-CSF alone, supporting its potential for developing new strategies for glioma treatment. Full article

Rolling bearings are critical and vulnerable components in mechanical equipment and are prone to various types of damage during operation. Consequently, rolling bearing fault diagnosis is of significant engineering importance. In recent years, deep learning-based approaches have achieved considerable progress in intelligent bearing fault diagnosis. However, existing models still suffer from several limitations, including insufficient feature extraction under noisy conditions, limited diagnostic accuracy, high computational cost, and low operational efficiency. To address these challenges, an intelligent rolling bearing fault diagnosis method based on an ascending-dimensional convolutional neural network (ADCNN) is proposed. Compared with conventional neural networks, the proposed ADCNN features a more compact model size, improved noise robustness, and higher diagnostic accuracy. A large convolutional kernel is introduced in the first layer to enhance noise immunity, while an ascending-dimensional module is employed to reduce the number of network parameters and improve feature extraction capability. In addition, a reduced linear transformation layer (RLTL) is incorporated to further achieve a lightweight architecture. Experimental results on the Case Western Reserve University (CWRU) dataset and a self-designed test dataset demonstrate that the proposed ADCNN achieves superior fault diagnosis performance under different noise environments while maintaining computational efficiency and model compactness. Full article

Radiation exposure from environmental sources, medical procedures, or space exploration poses considerable risks to human health, with profound effects on immune function and inflammatory responses. Radiotherapy (RT) is a cornerstone of modern cancer treatment, leveraging ionizing radiation to induce DNA damage and tumor cell death. However, its biological effects extend beyond direct cytotoxicity, exerting complex and context-dependent influences on both innate and adaptive immunity. Ionizing radiation can enhance antitumor immune responses by promoting tumor antigen release, activating dendritic cells, and augmenting cytotoxic T-cell priming. Conversely, it can also induce immunosuppressive mechanisms, including lymphocyte depletion, regulatory T-cell expansion, immune checkpoint upregulation, and chronic inflammatory signaling, which may limit therapeutic efficacy. These immune effects are critical for optimizing RT protocols, particularly in the era of immunotherapy, where immune modulation plays a pivotal role in treatment efficacy. This review summarizes the current knowledge concerning how radiation induces immune and inflammatory responses in cells and tissues; focuses on key molecular pathways such as the DNA damage response, cGAS–STING signaling, and immune checkpoint modulation; and discusses their clinical implications. These findings provide potential therapeutic strategies for cancer treatment by harnessing the immunomodulatory potential of radiation while reducing adverse effects and for the prevention and treatment of radiation-related diseases. Full article

The immune system maintains homeostasis through coordinated innate and adaptive responses, and its imbalance increases disease susceptibility. The immunomodulatory effects of 6-methoxykaempferol (6MK), a methoxylated flavonoid found in sweet cherries, were studied in a mouse model of cyclophosphamide (CPA)-induced immunosuppression. The expression of key signaling proteins in the NF-κB and MAPK pathways was studied to explore the underlying molecular mechanisms. The Toll-like receptor-4/myeloid differentiation factor-2 receptor complex (TLR4/MD2), which can stimulate the immune response by activating these pathways, was used to study possible interactions with 6MK using docking analysis. 6MK administration significantly restored immune organ integrity (spleen up to 15.1% and thymus up to 16.8%), enhanced NK cell function (up to 43.8%), promoted T (up to 24.5%) and B cell proliferation (up to 26.4%), increased pro- and anti-inflammatory cytokine (IL-1β, IL-6, TNF-α, IL-4, IL-10, and TGF-β) levels, and elevated NO (up to 25.6%) and immunoglobulin (IgG, IgA, and IgM) concentrations. Additionally, 6MK upregulated antioxidant enzymes (CAT, HO-1, and SOD) and reactivated suppressed NF-κB and MAPK pathways. The docking-supported hypothesis, based on putative interactions and the estimated free energy of binding, suggests that 6MK possesses agonistic potential for the TLR4/MD2. Changes in the gut microbiome due to 6MK treatment, such as an increase in alpha diversity, abundance of Dorea longicatena, and the upregulation of formaldehyde-consuming pathways, may also contribute to immune enhancement. These findings show that 6MK may alleviate immunosuppression, suggesting its potential for future studies targeting immune-related diseases and conditions. Full article

Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium–phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1α,25-dihydroxyvitamin D₃ (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental “super-agonists”, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications. Full article

Background: Respiratory bacterial infections represent a major health challenge in swine production, highlighting the need for novel immunomodulatory strategies that enhance host resistance. In this study, we investigated whether porcine intestinal lactobacilli could modulate the gut–lung axis and improve respiratory innate immunity in a mouse model of Streptococcus pneumoniae infection, as a surrogate of Streptococcus suis pneumonia. Methods: Three strains of Ligilactobacillus salivarius (LAFF998, LAFF1071, and LAFF1095) were orally administered to Swiss mice prior to pneumococcal challenge. The resistance to the infection, the lung damage and the respiratory innate immune response were evaluated. Results: Only strain LAFF998 significantly reduced pulmonary bacterial loads, prevented bacteremia, and attenuated lung injury. This protective effect was associated with selective modulation of respiratory immunity, characterized by reduced neutrophilic inflammation, increased lymphocyte recruitment, and enhanced activation of alveolar macrophages expressing MHC-II. LAFF998 markedly increased the production of IFN-β, IFN-γ, IL-6, IL-10, and IL-27 in the respiratory tract, without inducing excessive inflammatory damage. Ex vivo and in vitro analyses confirmed that alveolar macrophages from LAFF998-treated mice exhibited a primed phenotype with heightened cytokine responses to pneumococcal stimulation. In contrast, strains LAFF1071 and LAFF1095 failed to confer protection or significantly modulate respiratory immune responses. Conclusions: These findings demonstrate a strict strain-dependent effect among porcine L. salivarius isolates and identify LAFF998 as a potent immunobiotic capable of enhancing respiratory innate immunity through the gut–lung axis. This work supports further studies of LAFF998 as an immunobiotic strategy for the prevention of respiratory infections in pigs. Full article

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD. Full article

Background: Alterations of epithelial barrier integrity and immune response play a key role in the pathogenesis of allergic diseases and represent promising targets for nutritional interventions. Selected postbiotics and plant-derived compounds have been proposed as potential modulators of epithelial barrier and immune function. Methods: We investigated the effects of a novel food supplement combining heat-inactivated Lacticaseibacillus rhamnosus GG, butyrate, Quercetin, and Perilla frutescens extracts on epithelial barrier function and innate immunity in an experimental model of the human epithelial gut barrier. Results: Exposure to the food supplement resulted in epithelial barrier integrity enhancement, consisting of increased transepithelial electrical resistance, tight-junction protein expression, mucus production, and enterocyte differentiation. Moreover, the formulation markedly stimulated the expression of the innate immunity peptides β-defensin-2 and cathelecidin LL-37. Conclusions: The novel food supplement induces a beneficial modulation of the epithelial gut barrier and immune response. These findings support its potential use as a functional food strategy to restore mucosal homeostasis and to promote immune tolerance in allergic diseases. Full article

The ocular surface is a neuro–epithelial–immune unit in which corneal innervation is essential for maintaining tissue integrity and visual function. Sensory nerves regulate reflex tearing and blinking, provide trophic support, and modulate local immune responses. Nerve injury resulting from trauma, surgery, infection, systemic disease, or chronic inflammation disrupts epithelial homeostasis and may lead to neurotrophic keratopathy, neuropathic pain, and pathological remodeling. Beyond classical neurotrophic disease, nerve dysfunction contributes to severe dry eye and immune-mediated cicatricial disorders. Depending on the neuro-inflammatory context, remodeling may evolve toward stromal thinning, as in keratoconus, or progressive fibrosis, as in ocular cicatricial pemphigoid. Blood-derived eye drops, including serum- and platelet-based formulations, represent biologically active therapies that support epithelial repair and nerve regeneration, although greater standardization is needed. Full article

Iron deficiency (ID) has emerged as a pivotal yet underrecognized factor in the pathogenesis of immune-mediated inflammatory skin diseases (IMISDs) such as psoriasis, atopic dermatitis, and hidradenitis suppurativa. Beyond its classical role in erythropoiesis, iron acts as a key modulator of immune cell activity, redox balance, and overall metabolic homeostasis. This review synthesises the latest evidence on the intricate relationship between systemic inflammation, disturbances of iron metabolism, and immunometabolic imbalances that underline the pathogenesis of IMISDs. Findings indicate that chronic inflammation drives functional iron deficiency through IL-6–hepcidin-mediated sequestration of iron, resulting in reduced bioavailability and altered mitochondrial activity in immune and epithelial cells. This imbalance is associated with excessive and chronically enhanced oxidative and inflammatory responses of these cells, further advancing inflammation, anaemia of chronic disease, and disturbances of tissue repair. Moreover, emerging evidence supports an “iron-skin axis,” and suggests that skin cells, particularly epidermal keratinocytes, are actively involved in the regulation of iron pathways. Collectively, these insights position iron homeostasis as a missing link between systemic inflammation, immunometabolic imbalance, and disease burden in IMISDs. Full article

Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism and a hypermetabolic state involving complex endocrine, metabolic, and immune interactions. Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide involved in energy balance, neuroendocrine signaling, and neuroimmune modulation; however, its circulating levels and clinical relevance in GD remain unclear. In this single-center prospective study, serum CART levels were evaluated in 44 patients with GD and 44 age- and sex-matched healthy controls. Associations with thyroid function, autoimmune markers, metabolic parameters, and thyroid ultrasound heterogeneity were analyzed. Serum CART concentrations were measured using an enzyme-linked immunosorbent assay, and clinical, biochemical, and ultrasonographic data were recorded. Serum CART levels did not differ significantly between GD patients and healthy controls. However, within the GD group, CART levels varied significantly according to thyroid ultrasound heterogeneity, with lower levels observed in patients with severe parenchymal heterogeneity. Serum CART levels showed positive correlations with body mass index and insulin resistance indices, while inverse correlations were observed with thyrotropin receptor antibody and anti-thyroid peroxidase antibody levels. No significant associations were identified between serum CART levels and circulating thyroid hormone concentrations. These findings suggest that serum CART may reflect metabolic and autoimmune heterogeneity rather than hypothalamic–pituitary–thyroid axis activity in GD, supporting its role as a context-sensitive, hypothesis-generating biomarker. Full article