Search Results (31,810)

Background: Type 2 inflammatory diseases are among the most common chronic inflammatory conditions in childhood and represent a growing global health burden. Increasing evidence suggests that early-life nutritional exposures may influence immune programming and allergic disease development. This Position Paper aims to summarize the current evidence regarding the immunomodulatory role of polyunsaturated fatty acids (PUFAs), particularly omega-3 long-chain fatty acids, in the prevention of allergic diseases during early life. Methods: A scoping literature review and consensus process were conducted to map biological mechanisms and clinical evidence linking omega-3 PUFAs with allergic disease prevention. This document analyzed experimental, observational, and randomized controlled studies evaluating maternal prenatal/lactational omega-3 exposure. The clinical evidence was qualitatively appraised using study-design-specific Joanna Briggs Institute (JBI) Critical Appraisal Tools. Particular attention was given to immune modulation, inflammatory pathways, epithelial barrier function, gut microbiota interactions, and the ferroptosis–immune–metabolic axis. Results: Omega-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert immunomodulatory and anti-inflammatory effects through multiple mechanisms, including specialized pro-resolving mediator production, regulation of T-helper cell responses, cytokine modulation, maintenance of epithelial barrier integrity, and microbiota interaction. Emerging evidence also supports their involvement in oxidative stress and ferroptosis regulation. Current clinical evidence, particularly from higher-quality prenatal randomized trials and evidence syntheses, suggests that adequate maternal omega-3 intake during pregnancy and lactation may reduce the risk of respiratory allergic outcomes, especially wheezing and asthma, in selected offspring. Conclusions: Adequate omega-3 PUFA intake, such as 2 g/die, during critical windows of immune maturation may represent a valuable strategy for the primary prevention of allergic diseases. Current evidence most strongly supports supplementation during pregnancy and lactation, particularly in populations with low dietary omega-3 intake or increased allergic risk. Omega-3 supplementation should be considered within a broader multifactorial preventive approach aimed at promoting immune tolerance and reducing the future burden of allergic diseases. Full article

Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal–fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets. Full article

Survivin is a cancer-associated inhibitor of apoptosis protein (IAP) that can suppress both extrinsic and intrinsic apoptotic pathways. IAPs typically prevent programmed cell death by binding to caspases, but whether survivin behaves as a canonical IAP or can protect cells from death by alternative means has not been fully investigated. Here, we report a novel interaction between survivin and the mitochondrial outer membrane protein, VDAC2, which we show is an indirect association potentially mediated by Bcl2-family members. This novel finding suggests survivin can suppress mitochondrial-mediated apoptosis upstream of caspases and could open a new avenue for targeting survivin in anti-cancer therapy regimes. Full article

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation and survival of neoplastic plasma cells (PCs) within the bone marrow (BM), where disease progression is critically supported by interactions with the BM tumor microenvironment (TME). Despite significant advances in therapeutic strategies, MM remains incurable, underscoring the need for improved preclinical models to better understand the disease biology and therapeutic response. This review summarizes current and emerging MM treatment approaches and critically examines the development of models designed to more accurately recapitulate interactions between MM-PCs and the surrounding BM niche. We describe established and emerging modeling platforms, with emphasis on advanced three-dimensional (3D) culture systems and highlight their unique contributions to the preclinical assessment of both existing and novel therapies. The advantages of 3D models, including in vitro and in silico systems, over traditional two-dimensional (2D) models are discussed, alongside a comparative evaluation of scaffold-free and scaffold-based approaches. In addition, the benefits and recent advances in the customization of BM niche simulation using microfluidic technologies and organ-on-a-chip platforms are reviewed. The application of 3D models in MM research is increasingly enabling the study of disease pathogenesis, progression, drug resistance and precision-medicine approaches (informed by biomarker discovery). Although standardized preclinical approaches for evaluating MM therapeutics are currently lacking, the growing imperative to reduce reliance on preclinical animal models highlights the importance of alternate systems. Consequently, the development and adoption of physiologically relevant models that accurately recapitulate MM-PC interactions with the BM TME will be critical for advancing future therapeutic strategies in MM. Full article

Lactoferrin (LF)-derived peptides (LDPs) are short cationic and amphipathic fragments generated primarily from the N-terminal lobe of LF through pepsin-mediated proteolytic processes. The best-characterized LDPs include lactoferricin (LFcin), lactoferrampin (LFampin), and LF1‒11. In addition to these native peptides, a growing range of engineered LDPs has been developed by modifying the LFcin-derived RRWQWR motif through the incorporation of non-natural amino acids, cyclization, multimerization, and conjugation with chemotherapeutic agents. LDPs have garnered significant interest as potential anticancer peptides due to their ability to preferentially engage with the surfaces of malignant cells and initiate various tumor-suppressive mechanisms. This review article provides an overview of the principal classes of LDPs and elucidates how structural features influence membrane interaction, selectivity, intracellular targeting, apoptotic pathways, and immune modulation. It also discusses current mechanistic insights and examines the major challenges and opportunities for translating innovative LDPs into clinically useful cancer therapeutics. Full article

Inulin-type fructans are widely recognized as functional polysaccharides with prebiotic properties, while plant polyphenols represent one of the most important classes of natural antioxidants. Increasing evidence demonstrates that interactions between dietary fibers such as inulin and phenolic compounds significantly influence antioxidant capacity, bioavailability, and physiological activity. The present review integrates recent advances regarding the chemical structure of inulin, extraction sources, molecular interactions with polyphenols, and implications for antioxidant activity in functional foods and nutraceuticals. Experimental studies indicate correlations between inulin concentration and antioxidant parameters such as DPPH, FRAP, SOD and CAT activities. Furthermore, physicochemical interactions between cell wall polysaccharides and polyphenols influence the stability, release kinetics and bioefficacy of antioxidant compounds. These findings support the potential development of optimized functional formulations combining inulin-rich plant extracts with polyphenol sources for improved health benefits. The literature was identified through searches of PubMed, Scopus and Web of Science databases (2000–2026). Full article

The COVID-19 pandemic highlighted the urgent need to develop effective and broad-spectrum antiviral therapies against coronaviruses. One strategy to address this concern is a combination therapy using repurposed drugs against zoonotic viruses with pandemic potential. We previously demonstrated that the combination of Remdesivir and Ivermectin is highly potent and synergistic in inhibiting the replication of murine hepatitis virus (MHV) in RAW264.7 macrophages. This study investigated the interactions between the drug combination, coronavirus and host by proteomics and RNA sequencing of MHV-infected H2.35 murine liver epithelial cells. Time-of-addition and time-of-removal assays suggested that the drug combination likely affected the synthesis of viral RNA and viral protein. This combination drastically diminished the live virus titer greater than the respective monotherapies in MHV-infected H2.35 cells (by ~4 log₁₀), as well as in SARS-CoV-2-infected VeroE6 cells and human nasal epithelial cells. Proteomic and transcriptomic analyses revealed that viral protein and RNA levels were significantly depressed upon combination treatment. The drug combination exhibited considerable negative effects upon host RNA processes and resulted in the upregulation of host protein processes (e.g., response to unfolded protein; protein insertion into ER membrane). Molecular pathways affected by the combination treatment were markedly distinct from the monotherapies and indicated that Ivermectin enhances Remdesivir by modulating critical host processes to synergistically exert its inhibitory effect on the coronavirus replication cycle. Full article

Bacterial infections pose a serious threat to human health, and antibiotics remain the first-line therapeutic agents in clinical practice. However, the vast majority of antibiotics lack the ability to penetrate cell membranes, which severely limits the number of clinically available options for treating intracellular bacterial infections. Developing efficient intracellular antibiotic delivery strategies is therefore of considerable clinical significance, both for reducing antibiotic dosage and for expanding the repertoire of drugs applicable to intracellular infections. To address this challenge, we constructed a protein-based delivery platform mediated by a cell-penetrating miniprotein for efficient intracellular antibiotic delivery. In this system, bovine serum albumin (BSA), which possesses broad antibiotic-binding capability, was employed as the drug carrier, while the cell-penetrating miniprotein ZF5.3, which is capable of endosomal escape, served as the transmembrane delivery mediator. ZF5.3 was conjugated to BSA via a bioorthogonal reaction, and ceftriaxone (CRO) was selected as the model antibiotic to construct a nanoscale delivery system. The binding interaction between CRO and BSA was characterized using UV-Vis, HPLC, and molecular docking techniques. The assembly of the ZF5.3–BSA delivery platform was confirmed by UV-Vis absorption spectroscopy and gel electrophoresis. Intracellular delivery efficiency was evaluated by confocal fluorescence imaging and flow cytometry, and the results demonstrated that ZF5.3 conjugation enhanced intracellular protein delivery efficiency by over 5-fold. Fluorescence co-localization analysis revealed that ZF5.3-mediated cargo is mainly distributed in the cytoplasm and does not completely co-localize with lysosomal markers, suggesting its ability to effectively escape from lysosomes. An intracellular infection model using Staphylococcus aureus was established. Colony-forming unit (CFU) counting experiments confirmed that the delivery system significantly enhanced the intracellular antibacterial activity of ceftriaxone. CCK8 cytotoxicity assays confirmed that the system is non-toxic to cells. Full article

Vibrio tubiashii infection has led to several Babylonia areolata pandemics on the southeast coast of China, yet the immune response of the ivory shell against V. tubiashii and the specific pathogen–host interaction remain unclear. This dynamic study aimed to characterize the response of B. areolata to V. tubiashii infection with the use of pathology, transcriptomics, an enzymatic assay, and inflammatory cytokines. Hepatopancreatic cells showed marked vacuolar degeneration with intact cell membrane and extensive cytoplasmic vacuolization after infection. The dynamic transcriptome of the hepatopancreatic tissue was analyzed by RNA-seq after V. tubiashii infection, and a total of 2733 (3 h), 5610 (24 h), 3323 (48 h), and 418 (72 h) differentially expressed genes (DEGs) were identified during infection. The GO and KEGG analyses showed that the DEGs were enriched in metabolic regulation, lysosome, and multiple immune-related pathways such as the MAPK signaling pathway. The immune response of B. areolata was distinct, where the early stage of immune response (3 h) showed binding, focal adhesion, and apoptosis, as well as an activated antioxidant system. Here, expression of TNF-α, IL-1, and IL-8 was significantly increased in the hepatopancreas, whereas expression of IL-6 and IL-17 increased afterward. During the middle stage (24 h and 48 h), a large number of DEGs were suppressed, especially those associated with metabolism and lysosomes, although their expression returned to normal during prolonged infection (72 h). The PPI network showed that ppp2, atp6, and sos1 were the top immune-related DEGs during infection. Key infection-related and time-course-related genes were analyzed by WGCNA. This study illustrates that oxidative stress, inflammation, and apoptosis are strategies of the hepatopancreatic immune response in B. areolata against V. tubiashii infection and enlightens conservation and production by furthering our understanding of gastropod immunity. Full article

Elucidating the interactions among microbial communities in the Sichuan paocai fermentation system is of great significance for ensuring the safety and quality of paocai. In this study, the interaction between Bacillus subtilis Y61 and Weissella paramesenteroides (CWP) was preliminarily verified through the culture of CWP using the cell-free supernatant derived from Y61. Building on this, a transwell chamber was employed to spatially isolate the two bacteria. Combined with transcriptomic and metabolomic profiling, the underlying interaction mechanism was revealed. Weissella paramesenteroides (CWP) exhibited enhanced growth in the cell-free supernatant of Bacillus subtilis Y61, confirming a cross-feeding relationship between the two strains. In the transwell chamber, the promoting effect was most significant when Weissella paramesenteroides (CWP) was in the upper compartment and Bacillus subtilis Y61 in the lower compartment. Transcriptomic analysis showed that Weissella paramesenteroides (CWP) significantly upregulated genes involved in fatty acid synthesis and metabolism while downregulating those related to amino acid anabolism (p < 0.05). Metabolomic analysis further revealed that metabolites secreted by Bacillus subtilis Y61, including the key metabolites arginine and isovaleric acid, were markedly depleted during co-culture. Exogenous supplementation assays revealed that the combination of 0.1 g arginine and 2 mg isovaleric acid exhibited the strongest growth-promoting effect on Weissella paramesenteroides (CWP). Collectively, these results demonstrated that Bacillus subtilis Y61 promoted the growth of Weissella paramesenteroides (CWP) through cross-feeding via the extracellular secretion of the key metabolites arginine and isovaleric acid. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC. Full article

Weaning stress and immune challenges can negatively affect the health and performance of young pigs by inducing inflammatory responses. Functional protein sources, such as enzymatically hydrolyzed whole blood (EHB), may help alleviate inflammation and improve immune status during stressful conditions. A total of 20 late-weaned pigs [Landrace × Yorkshire × Duroc], 42 days of age, with an initial body weight of 15.34 ± 1.17 kg, were used in a 2-week experiment. Pigs were allotted to a 2 × 2 factorial arrangement with two dietary protein sources [plasma protein (PP) and/or EHB] and two immune challenges (saline or LPS). The four experimental groups were as follows: (1) Plasma-Sal, PP diet + saline injection; (2) Plasma-LPS, PP diet + LPS injection (100 μg/kg BW); (3) EHB-Sal, EHB diet + saline injection; and (4) EHB-LPS, EHB diet + LPS injection (100 μg/kg BW). Each treatment consisted of five replicate pens with one pig/pen. Pigs fed either protein diet with and without LPS showed no (p > 0.05) difference in their nutrient digestibility and microbial population. However, pigs challenged with LPS exhibited a higher (p < 0.05) rectal temperature, with significant differences observed at 6 h and 12 h post-injection (p < 0.001). Dietary effects (p < 0.05) were observed for IL-6 and TNF-α concentrations, with pigs fed EHB exhibiting lower values compared with those fed the PP diet following LPS challenge. Consistent with an inflammatory response, pigs challenged with LPS showed elevated (p < 0.05) IL-6 and TNF-α concentrations, together with increased white blood cell and lymphocyte counts, at 12 h post-challenge. Moreover, significant (p < 0.05) diet × LPS interactions were detected for IL-6 and TNF-α concentrations at 6 h post-challenge, indicating that dietary EHB attenuated the inflammatory response induced by LPS. In summary, a diet formulated with EHB showed a reduced effect of LPS challenge in pigs, making it promising as a functional dietary protein source for improving immune resilience in weaned piglets. Full article

Ketoprofen (KET) is a non-steroidal anti-inflammatory drug frequently detected in surface waters and effluents, with the potential to impact trophic base organisms. This study evaluated the toxicity of KET, in its active pharmaceutical ingredient (API) form and in four commercial formulations (KET-1, KET-2, KET-3, and KET-4), on two freshwater species: the cyanobacterium Microcystis novacekii and the microalga Chlorella vulgaris. Cell growth assays, performed under acute (4 days) and chronic (14 days) conditions, showed that the API KET was the most toxic compound, especially for M. novacekii, with a chronic EC50 of 1.35 mg/L. The commercial formulations presented distinct toxicity profiles, suggesting the influence of excipients and synergistic or antagonistic interactions. For C. vulgaris, low acute toxicity was observed, with increased chronic effects at high concentrations and possible hormetic response at low doses. Risk quotient (RQ) calculations, based on environmental concentrations of KET, indicated low risk in surface and drinking water, but high risk in untreated hospital and wastewater treatment plant effluents, especially for M. novacekii. The results show that the complete formulation, exposure time, and target species are critical factors in the ecotoxicological risk assessment of pharmaceuticals in freshwater environments. Full article

Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed “regenerative inflammation,” in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF–IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions. Full article

Background: The glucocorticoid receptor NR3C1 exhibits antiepileptic properties, but the mechanisms governing its stability during epileptogenesis remain elusive. This study investigated whether the E3 ubiquitin ligase TRIM8 regulates neuronal hyperexcitability and epileptic activity by modulating NR3C1. Methods: We established an in vivo epilepsy model via intrahippocampal kainic acid (KA) injection and an in vitro epileptiform model using Mg²⁺-free artificial cerebrospinal fluid in primary hippocampal neurons. The roles of TRIM8 and NR3C1 were assessed using in vivo and in vitro gain- and loss-of-function approaches, alongside co-immunoprecipitation, Western blotting, immunofluorescence and whole-cell patch-clamp recording. Results: TRIM8 is significantly upregulated in hippocampal and temporal lobe neurons in epileptic mice. TRIM8 was markedly upregulated in the hippocampal neurons of epileptic mice, inversely correlating with NR3C1 levels. Mechanistically, TRIM8 interacted with NR3C1, promoting its polyubiquitination and proteasomal degradation. This TRIM8-mediated NR3C1 reduction enhanced the phosphorylation of AMPA receptor (AMPAR) subunits GluR1 (Ser831) and GluR2 (Ser880) without affecting total receptor expression. In vitro, TRIM8 overexpression exacerbated calcium dysregulation, neuronal injury, and AMPAR phosphorylation; crucially, concurrent NR3C1 overexpression rescued these effects. In vivo, knockdown of TRIM8 significantly reduced seizure frequency, prolonged the latency to the first Stage III seizure, shortened average seizure duration, and decreased total seizure burden in KA-induced epileptic mice. Electrophysiologically, TRIM8 overexpression significantly increased the frequency of spontaneous action potentials and amplitudes of spontaneous excitatory postsynaptic currents under Mg²⁺-free conditions. Furthermore, in vivo knockdown of TRIM8 attenuated KA-induced seizure severity, restored NR3C1 protein stability, and suppressed aberrant AMPAR phosphorylation in the hippocampus. Triple immunofluorescence staining showed that KA-induced epilepsy increased TRIM8 but decreased NR3C1 immunoreactivity in NeuN⁺ hippocampal neurons, and TRIM8 knockdown reversed these changes. Conclusions: TRIM8 acts as a critical driver of epileptiform activity by targeting NR3C1 for degradation, thereby disinhibiting AMPAR phosphorylation and enhancing network hyperexcitability. The TRIM8-NR3C1-AMPAR axis emerges as a previously unrecognized molecular pathway in epileptogenesis, highlighting its potential as a promising therapeutic target for epilepsy. Full article