Search Results (62)

Recurrent pregnancy loss (RPL) continues to be a significant challenge in reproductive medicine, particularly in women for whom standard examinations do not reveal a conclusive underlying reason. There is growing evidence that several instances may result from nuanced alterations in the endometrial milieu, particularly with decidualization and maternal–fetal immune tolerance. In recent years, vitamin D has gained recognition for its significance in early pregnancy, serving not only as a regulator of calcium metabolism but also as an active contributor to endometrial and immunological functions. The human endometrium exhibits the vitamin D receptor (VDR) and the enzyme CYP27B1, facilitating the local activation and signaling of vitamin D inside the uterine milieu. Experimental investigations have shown that vitamin D influences many processes critical for effective implantation and placentation, including stromal cell differentiation, cytokine equilibrium, trophoblast invasion, oxidative stress responses, and immune cell communication. Aberrant vitamin D signaling has been associated with heightened inflammatory activity, impaired decidual transformation, altered uterine natural killer cell functionality, and alteration of the Treg/Th17 equilibrium, all of which have been implicated in recurrent pregnancy loss. Concurrently, there is an increasing emphasis on the association between vitamin D and mitochondrial function as well as oxidative stress in decidual and endometrial cells. Interruption of these pathways may influence implantation and early embryonic development by impacting cellular metabolism and immunological control at the maternal–fetal interface. The clinical interest in vitamin D supplementation for women experiencing repeated reproductive failure is increasing; nevertheless, the existing results are conflicting, mostly due to the predominance of research focusing on circulating vitamin D levels rather than localized tissue-specific processes. Our review encapsulates new findings about the function of vitamin D in endometrial biology and reproductive immune regulation, emphasizing its involvement in decidualization, inflammatory signaling, oxidative stress, and maternal–fetal immunological tolerance in recurrent pregnancy loss. The potential ramifications for assisted reproduction and forthcoming tailored therapy techniques are also examined. Full article

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8⁺ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8⁺ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8⁺ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8⁺ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8⁺ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8⁺ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8⁺ T cells. Conversely, activated CD8⁺ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8⁺ T cell-derived vesicles. Full article

Frailty and osteoarthritis (OA) frequently coexist in older adults, yet the extent to which they share molecular programs across tissues remains unclear. We integrated bulk transcriptomics, peripheral immune and OA meniscal single-cell atlases, inferred cell–cell communication, and an in vitro myeloid–chondrocyte conditioned-medium model. Frailty-associated vastus lateralis and OA synovium shared a 16-gene program enriched for inflammatory and migratory processes, which was refined by protein–protein interaction analysis into a 15-gene hub module (Hub-15). Donor-aware pseudobulk analysis showed coordinated Hub-15 upregulation in CD8 T, natural killer, B, and monocyte/macrophage-like cells, with the highest scores in monocyte/macrophage populations. In the meniscal atlas, donor-level analysis of 7 normal and 6 OA donors identified a 20.5 percentage point lower proportion of inflammatory/stress cells and a 17.3 percentage point higher proportion of fibrochondrocyte-like cells in OA (both false discovery rate = 0.010), whereas state-specific Hub-15 differences were not significant after correction. Exploratory communication analysis nominated directionally consistent candidate myeloid-to-structural signaling axes, although none remained significant after multiple-testing correction. Conditioned medium from cytokine-primed THP-1 cells elicited inflammatory and matrix-catabolic responses in C28/I2 cells. These findings identify a cross-tissue, leukocyte-shared, and myeloid-enriched inflammatory program that converges across independent frailty and OA cohorts, providing a hypothesis-generating framework for future mechanistic testing. Full article

With the rapid expansion of intensive aquaculture, the frequent outbreak of diseases and the overuse of antibiotics have become increasingly critical issues. Therefore, developing green and efficient antibiotic alternatives is essential for the sustainable growth of the industry. As a novel probiotic, Bacillus velezensis has shown great potential in improving the disease resistance of aquatic animals, owing to its excellent spore-forming ability, broad-spectrum antibacterial activity, and immunoregulatory functions. This paper systematically reviews the main mechanisms by which B. velezensis enhances disease resistance in aquatic animals, including directly inhibiting pathogens through the secretion of various lipopeptides and polyketides such as surfactin, iturin, and fengycin; interfering with pathogen quorum sensing systems via quorum quenching enzymes, thereby suppressing virulence factor expression and biofilm formation; modulating intestinal microbiota structure to increase the abundance of beneficial bacteria while reducing pathogenic proliferation; and activating the non-specific immune system of the host to upregulate immune-related indicators such as acid phosphatase, superoxide dismutase, and key cytokines (such as IL-1β, TNF-α). In addition, this review summarizes the application effects of B. velezensis on improving aquaculture water quality and promoting host growth. Furthermore, the potential ecological impacts on natural microbial communities and strain-dependent biosafety risks are evaluated. Finally, current research limitations—such as strain-specific functional differences, insufficient in-depth analysis of mechanisms, and inconsistent application outcomes—are discussed. Future prospects for promoting the efficient and stable application of B. velezensis in aquaculture through strategies including gene editing, multi-omics integration, and precise formulation compounding are also proposed. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Successful embryo implantation requires dynamic, bidirectional communication between a developmentally competent blastocyst and a receptive endometrium, integrating hormonal, molecular, and immunologic signals. Increasing evidence indicates that endometrial receptivity is critically dependent on a specialized immune microenvironment that supports trophoblast invasion while maintaining maternal tolerance. This review synthesizes current knowledge on the immunologic regulation of implantation, with emphasis on uterine natural killer (uNK) cells, regulatory T cells (Tregs), macrophages, dendritic cells, and cytokine networks. We further examine intracellular signaling pathways—including JAK/STAT, PI3K/AKT, NF-κB, and MAPK—that integrate immune and decidual responses. The bidirectional embryo–endometrium dialogue is explored through embryo-derived mediators such as human chorionic gonadotropin (hCG), cytokines, growth factors, and extracellular vesicles. The endometrium is increasingly recognized as a biosensor of embryo quality, selectively supporting viable embryos. Disruption of this complex communication network is implicated in recurrent implantation failure and early pregnancy loss. Despite substantial mechanistic advances, clinical translation remains limited. Emerging strategies, including immune profiling, microbiome modulation, and extracellular vesicle-based diagnostics, hold promise for precision reproductive medicine. Full article

Background/Objectives: Homeostatic (nervous, immune and endocrine) systems and their communications network are crucial for health and aging rate. We previously reported behavioral and peritoneal leukocyte function alterations and oxidative-inflammatory stress in young female triple-transgenic (3xTg) mice for Alzheimer’s disease (AD). Here, the deterioration of the homeostatic systems and their interplay was investigated, in an integrated way, at prodromal stages and in both sexes of 3xTg-AD mice. Methods: An integrative analysis of the behavioral profile, peripheral immune splenic and thymic leukocyte functions, splenic oxidative-inflammatory state, and plasmatic corticosterone in both sexes of 3xTg-AD mice at 4 months of age was compared to that of age- and sex-matched NTg counterparts. Results: The prodromal stage of 3xTg-AD, characterized by anxiety-like behaviors and disrupted exploration, was aligned with reduced chemotaxis, natural killer activity, and lymphoproliferation—especially in the spleen. In addition, 3xTg-AD mice exhibited lower anti-inflammatory (IL-10) and higher pro-inflammatory (IL-2, IL-1β, and TNF-α) cytokine concentrations and oxidative stress (higher oxidants and lower antioxidants). Several of these alterations displayed sex-dependent differences (worse in males). However, no differences in corticosterone were found. Conclusions: These findings suggest that neuroimmune and redox-inflammatory dysfunctions, indicative of premature aging, emerge at the prodromal stage of AD, preceding corticosterone changes, unveiling a time lag in the neuroimmunoendocrine alterations in these animals. They may act as early indicators of premature aging in AD pathology and provide potential targets for sex-specific prodromal intervention. Full article

The enteric nervous system (ENS) constitutes a highly organized and intricate neuronal network comprising two principal plexuses: myenteric and submucosal. These plexuses consist of neurons and enteric glial cells (EGCs). Neurons ensure innervation throughout the intestinal wall, whereas EGCs, distributed within the mucosa, contribute to epithelial barrier integrity and modulation of local inflammatory responses. The ENS orchestrates essential gastrointestinal functions, including motility, secretion, absorption, vascular regulation, and immune interactions with gut microbiota. Under physiological conditions, intestinal homeostasis involves moderate generation of reactive oxygen species (ROS) through endogenous processes such as mitochondrial oxidative phosphorylation. Cellular antioxidant systems maintain redox equilibrium; however, excessive ROS production induces oxidative stress, promoting EGCs activation toward a reactive phenotype characterized by pro-inflammatory cytokine release. This disrupts neuron–glia communication, predisposing to enteric neuroinflammation and neurodegeneration. Obesity, associated with hyperglycemia, hyperlipidemia, and micronutrient deficiencies, enhances ROS generation and inflammatory cascades, thereby impairing ENS integrity. Nevertheless, non-pharmacological strategies—including synthetic and natural antioxidants, bioactive dietary compounds, probiotics, and prebiotics—attenuate oxidative and inflammatory damage. This review summarizes preclinical and clinical evidence elucidating the interplay among the ENS, obesity-induced oxidative stress, inflammation, and the modulatory effects of antioxidant interventions. Full article

Toxin–antitoxin (TA) modules represent sophisticated regulatory networks that have evolved from simple plasmid maintenance factors into multifunctional genetic modules orchestrating bacterial stress responses, pathogenesis, and ecological adaptation. This review highlights a compelling correlation between the abundance of toxin–antitoxin (TA) modules and bacterial pathogenicity, as exemplified by Mycobacterium tuberculosis (M.tb), which encodes 118 TA loci—significantly more than the fewer than 10 found in closely related saprophytic species. The clinical significance of TA modules extends beyond traditional stress response roles to encompass antimicrobial persistence, where systems like VapBC and MazEF facilitate dormant subpopulations that survive antibiotic therapy while maintaining chronic infections. Recent discoveries have revealed TA modules as sophisticated bacterial defense mechanisms against bacteriophage infection, with DarTG and ToxIN systems representing novel antiviral immunity components that complement CRISPR-Cas and restriction–modification systems. The immunomodulatory capacity of TA modules demonstrates their role in host–pathogen interactions, where systems such as VapC12 in M.tb promote macrophage polarization toward permissive M2 phenotypes while inducing anti-inflammatory cytokine production. Large-scale genomic analyses reveal that TA modules function as drivers of horizontal gene transfer networks, with their signatures enabling accurate prediction of plasmid community membership and serving as determinants of microbial community structure. The biotechnological applications of TA modules have expanded to include genetic circuit stabilization, biocontainment device construction, and multi-species microbial community engineering, while therapeutic strategies focus on developing multi-target inhibitors against conserved TA protein families as promising approaches for combating drug-resistant bacterial infections. The evolutionary conservation of TA modules across diverse bacterial lineages underscores their fundamental importance as central organizing principles in bacterial adaptation strategies, where their multifunctional nature reflects complex selective pressures operating across environmental niches and host-associated ecosystems. This review provides an integrated perspective on TA modules as dynamic regulatory elements that support bacterial persistence, immune evasion, and ecological versatility, establishing them as genetic elements with truly “many faces and functions” in prokaryotic biology. Full article

Fungal communities in the gut influence host immunity, yet most studies have focused on cell wall components rather than genetic materials. Here, we explore how fungal genomic DNA (gDNA) from Candida albicans, Saccharomyces cerevisiae, and Cryptococcus neoformans modulate immune responses in human CD4⁺ T cells, murine splenocytes, and THP-1-derived macrophages. We find that C. albicans gDNA promotes the development of regulatory T cells and increases IL-10, fostering immune tolerance and preserving CD4⁺ T cell viability in an inflammatory setting. S. cerevisiae gDNA induces moderate Treg responses with restrained effector T cell expansion and higher checkpoint gene expression, entirely consistent with its commensal nature. In contrast, C. neoformans gDNA elicits a strongly inflammatory profile, promoting Th1/Th17 cells and driving high cytokine production. Mechanistically, C. albicans and S. cerevisiae gDNA dampen DNA-sensing pathways and enhance immune checkpoint molecules that act as brakes against overactivation, while C. neoformans gDNA robustly activates innate sensing pathways with limited checkpoint induction. These species-specific signaling profiles reveal that fungal gDNA itself can influence whether the immune system adopts a tolerant or inflammatory response toward fungi. This discovery highlights fungal genomic DNA as a previously underappreciated regulator of host–fungus interactions, offering new insight into commensal persistence, pathogenic invasion, and the potential for DNA-based antifungal interventions. Full article

Background and Objectives: Periodontitis is a common chronic inflammatory disease and a leading cause of tooth loss worldwide. Traditional diagnostic methods, such as probing and radiographic assessment, are retrospective and fail to detect ongoing disease activity. In recent years, salivary biomarkers and oral microbiome profiling have emerged as promising tools for earlier detection and precision-based management. The aim of this review is to synthesize current evidence on salivary and microbiome-derived biomarkers in periodontitis and to evaluate their translational potential in diagnostics and therapy. Materials and Methods: A narrative review was performed using PubMed, Scopus, and Web of Science to identify studies published between 2020 and 2025. Search terms included periodontitis, salivary biomarkers, oral microbiome, dysbiosis, and precision therapy. Priority was given to systematic reviews, meta-analyses, and translational studies that addressed diagnostic or therapeutic applications. Eligible publications included English-language original studies and reviews reporting on the diagnostic or therapeutic relevance of salivary or microbiome biomarkers in periodontitis. Results: Salivary biomarkers such as cytokines, matrix metalloproteinases (MMPs), oxidative stress markers, microRNAs, and extracellular vesicles (EVs) show consistent associations with disease activity and treatment outcomes. Oral microbiome studies reveal that both classical pathogens and community-level dysbiosis contribute to disease risk. Translational advances include chairside immunoassays, biosensors, lab-on-a-chip devices, and artificial intelligence (AI)-driven analyses. Biomarker-guided therapies—such as microbiome modulation, natural bioactive compounds, host-response modulation, and smart biomaterials—are being evaluated with increasing frequency in translational studies. Conclusions: By integrating salivary and microbiome biomarkers with novel diagnostic technologies and emerging therapies, this review complements existing systematic evidence and offers a translational roadmap toward precision periodontology. Full article

Neuroinflammation, driven by activated microglia, contributes to the progression of neurodegenerative diseases. Extracellular vesicles mediate intercellular communication and influence immune responses. Chrysin, a natural flavone found in fruits and propolis, has demonstrated anti-inflammatory effects. This study explored the immunomodulatory potential of chrysin-loaded EVs (EVs-Chry) derived from BV2 microglial cells. BV2 cells were treated with chrysin for 24 h to assess cytotoxicity and proliferation. EVs were isolated from treated and untreated cells, characterized by nanoparticle tracking analysis, and applied to naïve BV2 cells prior to LPS stimulation. Effects on cell morphology, migration, cytokine expression (IL-1β, IL-6), inflammasome activity (caspase-1), and apoptosis-related protein Bcl-xL were investigated. Our results show that EVs-Chry significantly reduced LPS-induced cell proliferation, restored resting microglial morphology, and reduced migratory capacity. Furthermore, co-treatment with EVs-Chry and LPS reduced pro-inflammatory cytokines such as IL-1β, IL-6, and caspase-1 expression while enhancing anti-apoptotic Bcl-xL levels, indicating a shift toward an anti-inflammatory, neuroprotective micro-glial phenotype. Together, our results demonstrated that EVs-Chry have neuroprotective effects on LPS-induced microglial activation and modulate microglial responses to inflammatory stimuli, attenuating pro-inflammatory signaling and promoting cellular homeostasis. These findings support the therapeutic potential of EVs-Chry in the context of neuroinflammatory and neurodegenerative disorders. Full article

Objectives: The oral cavity hosts one of the most complex microbial communities in the body. A disruption of the balance favors the growth of pathogenic species, contributing to oral diseases. The rise in microbial resistance has limited the effectiveness of conventional treatments, shifting the interest to natural product-based alternatives. Given its superior bioavailability and bioactivity in other models, this study investigates the antifungal potential of a novel curcumin derivative, PAC (3,5-bis(4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone), and studies its impact on host–pathogen dynamics and host defense mechanisms. Methods: Candida albicans was used as the model organism. Viability, growth kinetics, and colony formation were evaluated using optical density, agar culture, and MTT assay. Biofilm formation was assessed through electron microscopy and total sugar quantification. The morphological transition from hyphae to the less virulent blastospore was monitored using an optical microscope. The gene expression of adhesion factors and host defense markers was analyzed using RT-PCR. Results: PAC impairs C. albicans viability and reduces virulence by compromising biofilm formation and ensuring phenotypic transition to a blastospore form. Also, PAC controls C. albicans growth via necrosis/ROS pathways. As a result, PAC appears to repress host–pathogen interaction by downregulating SAPs, EAP1, and HWP1 adhesion genes, thus relieving the need to activate gingival epithelial cell defense mechanisms. This is highlighted by recording baseline levels of IL-6, IL-8, and IL-1β cytokines and antimicrobial β-defensin peptides in the presence of less virulent candida forms. Conclusions: PAC effectively reduces C. albicans virulence by limiting biofilm formation and adhesion while minimizing inflammatory responses. These findings support its potential as a promising therapeutic agent for infectious disease control. Full article

Chronic alcohol consumption is a major contributor to gastric injury, yet current therapeutic strategies predominantly rely on chemical agents with limited efficacy and potential side effects. Natural products, with their multi-target biocompatibility and safety advantages, offer promising alternatives for gastric protection. We examined the phenolic compounds of Elaeagnus angustifolia honey (EAH) and investigated its prophylactic potential against ethanol-induced chronic gastric injury in mice. HPLC-DAD-Q-TOF-MS analysis showed that 21 phenolic compounds were tentatively and qualitatively identified in EAH, as well as 14 phenolic compounds. Moreover, gastric ulcer indices, histopathological morphology, oxidative stress markers (MDA, GSH, SOD), inflammatory mediators (NO, PGE2), and cytokine gene expression (TNF-α, IL-6, IL-1β, iNOS) were evaluated via enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR. Western blot was employed to assess COX-2 protein expression, while 16^S rRNA sequencing analyzed gut microbiota composition. The results demonstrated that EAH could play a role in gastric injury caused by long-term alcoholism by protecting gastric tissue structure, interfering with oxidative stress and inflammatory response, and remodeling the intestinal microbial community. Full article

The cytokine network plays a crucial role in regulating immune responses and facilitating intercellular communication. Cytokines are essential in numerous physiological and pathological processes. This study aimed to investigate associations between blood cell counts and a broad range of cytokines, chemokines, and growth factors. We included one hundred and sixty-five essentially healthy individuals in this study, which was approved by the Swedish Ethical Review Authority (Dnr 2015/378) and registered in EudraCT (2014-004235-39). Blood samples were collected for blood cell counts and analysis of cytokines, chemokines, and growth factors using the Proseek Multiplex Inflammation kit, Olink Bioscience, Uppsala, Sweden. Correlations between the different markers were calculated using Spearman rank correlations, adjusted for multiplicity and for multiple testing, with a significance threshold of p < 0.05. There were significant associations between platelet count and 23 cytokines, between white blood cell count and 8 cytokines, and between erythrocyte volume fractions and 19 cytokines. IL-6 had a central role within the cytokine network associated with platelets and was also associated with white blood cells and neutrophil cells. These findings emphasize the integrated nature of immune and hematological responses, where blood cell parameters are associated with systemic cytokine activity. The observed intercytokine associations, including cross-family interactions, may help to highlight regulatory pathways, providing potential targets for biomarker development and therapeutic intervention in immune-mediated conditions. Full article