Search Results (279)

The ruminal epithelium plays a central role in nutrient absorption, epithelial barrier function, and mucosal immune defense. However, the molecular mechanisms by which dietary Perilla frutescens seeds (PFS) regulate ruminal epithelial immunity remain poorly understood. This study investigated the transcriptomic responses of the sheep ruminal papilla to dietary PFS supplementation. Forty-five male Tan sheep were assigned to three dietary treatments (n = 15 per group): a low-concentrate diet (LC), a high-concentrate diet (HC), and the LC diet supplemented with 3% PFS (LC + PFS). After an 84-day feeding trial, ruminal papilla tissues from six animals per group were randomly subjected to RNA sequencing and integrated bioinformatic analyses, covering all three pairwise comparisons (LC vs. HC, HC vs. LC + PFS, and LC vs. LC + PFS). The LC vs. LC + PFS comparison served as the direct assessment of PFS effects under the same basal diet, whereas HC vs. LC + PFS was treated as a cross-dietary comparison. LC vs. HC yielded 387 differentially expressed genes (DEGs), HC vs. LC + PFS yielded 104 DEGs, and LC vs. LC + PFS yielded 33 DEGs, with predominant enrichment in metabolic and stress-adaptive pathways (AMPK, MAPK, PI3K-Akt). The latter were mainly associated with metabolic and structural pathways. Propionate and valerate were negatively correlated with several interferon-signaling and antigen-presentation genes. Collectively, the direct LC vs. LC + PFS comparison demonstrates that PFS supplementation under physiological conditions is associated with targeted metabolic modulation. Meanwhile, the cross-dietary HC vs. LC + PFS comparison reveals that, relative to high-concentrate feeding, the PFS-supplemented low-concentrate feeding regimen is transcriptionally associated with enhanced immune surveillance capacity in a non-inflammatory manner. These findings provide transcriptomic evidence supporting the potential of PFS as a modulator of ruminal epithelial homeostasis and offer a foundation for further investigation into its application as a functional feed ingredient. Full article

γδ⁺ intraepithelial lymphocytes (IELs) are persistently expanded in the intestinal epithelium of patients with active celiac disease (ACeD), but their functional profile during active inflammation remains poorly defined. This study investigated the expression of pro- and anti-inflammatory cytokines in γδ⁺ IELs isolated from the intestinal epithelium of ACeD patients at different stages of mucosal damage. Frozen jejunum sections were obtained from 14 ACeD patients (7 Marsh II and 7 Marsh III) and 10 treated celiac disease (CeD) patients. γδ⁺ IELs from ACeD biopsies and intestinal enterocytes (IEs) from treated CeD biopsies were isolated by laser capture microdissection on mirror sections, followed by RNA extraction and quantitative real-time RT-PCR analysis of IL-15, IL-17A, IL-21, IFN-γ, TNF-α, IL-10, and TGF-β. Foxp3 expression was assessed by immunohistochemistry. γδ⁺ IELs from Marsh III biopsies showed significantly increased mRNA levels of IL-15, IL-17A, IL-21, IFN-γ, and TGF-β compared with IEs, whereas IL-10 expression was significantly higher in Marsh II γδ⁺ IELs compared with Marsh III and IEs. IL-21 and TGF-β were also higher in Marsh III than Marsh II γδ⁺ IELs. All γδ⁺ IELs were Foxp3⁻. These findings indicate a stage-dependent functional polarization of γδ⁺ IELs in ACeD, with an IL-10–associated regulatory profile in Marsh II and a predominant pro-inflammatory cytokine signature in Marsh III. Full article

The rumen epithelium mediates nutrient absorption and mucosal defense in ruminants, whereas increased exposure to lipopolysaccharide (LPS) under high-concentrate feeding may induce epithelial inflammation and barrier injury. This study investigated whether Caragana korshinskii tannin (CKT) protects against LPS-induced injury in primary sheep rumen epithelial cells and whether TLR4/MyD88/NF-κB signaling is involved. Cells were pretreated with 5 μg/mL CKT for 18 h and then challenged with 5 μg/mL LPS for 6 h. TLR4 knockdown experiments were performed in a sheep rumen epithelial cell line for mechanistic investigation. LPS induced inflammatory cytokine production, oxidative stress, G0/G1 cell-cycle arrest, apoptosis, and reductions in tight-junction-related markers (p < 0.05). CKT pretreatment attenuated these changes, as reflected by lower ROS and MDA levels, increased antioxidant enzyme activities, reduced apoptosis, and improved the expression of selected tight-junction-related proteins (p < 0.05). CKT also suppressed LPS-recognition components and TLR4/MyD88/NF-κB pathway activation (p < 0.05). TLR4 knockdown weakened LPS-induced injury and reduced the additional protective effect of CKT. Overall, CKT may protect rumen epithelial cells against LPS-induced inflammatory injury partly by inhibiting TLR4/MyD88/NF-κB signaling. Full article

Current inflammatory bowel disease (IBD) therapies suppress immune pathways, yet epithelial recovery can remain incomplete. This review evaluates whether intestinal chloride and bicarbonate transport can support a distinct, adjunctive pharmacological strategy. Rather than cataloguing transport proteins, we compare the cystic fibrosis transmembrane conductance regulator (CFTR), SLC26A3/down-regulated in adenoma (DRA), and TMEM16A/ANO1 against an evidence hierarchy of human disease relevance, causal epithelial biology, pharmacological tractability, target engagement, functional rescue, and developability. CFTR and DRA form the most coherent module linking bicarbonate availability to mucin expansion, epithelial surface pH, fluid balance, and barrier organization, but their liabilities differ. CFTR is structurally and clinically druggable, yet its modulators are genotype-directed, and broad activation may worsen diarrhea. DRA has stronger evidence for a colonic barrier role and emerging support from human organoids, but no validated activator or stabilizer. TMEM16A has abundant chemical tools, yet uncertain selectivity, wide extra-epithelial expression, and no established disease-modifying role in IBD. No intervention has achieved mucosal healing through anion-transport rescue in IBD. We therefore define the decisive experiments required before translation: confirmation of persistent functional defects in human tissue, selective exposure-linked rescue in patient-derived epithelium, direct target engagement, and protection against hypersecretion or electrolyte imbalance. The evidence supports focused, mechanism-based evaluation of the CFTR-DRA axis rather than empirical repurposing. Full article

The gastrointestinal epithelium forms a critical barrier that regulates nutrient absorption while preventing the translocation of harmful luminal contents. Disruption of this barrier initiates a coordinated wound healing response involving epithelial restitution, proliferation, and differentiation. Focal adhesion kinase (FAK) is central to this process, regulating focal adhesion (FA) turnover and cytoskeletal dynamics required for epithelial migration. Activation of FAK via phosphorylation at tyrosine 397 (Y397) promotes cell motility, proliferation, and survival, whereas loss of function impairs mucosal repair and exacerbates tissue injury. Effective wound healing also requires tight regulation of reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (NRF2) pathway governs antioxidant defenses by inducing cytoprotective genes, including SOD1, CAT, GCLC, GCLM, and NQO1, restoring redox homeostasis and limiting inflammation. NRF2 deficiency results in increased oxidative stress, heightened inflammatory signaling, and delayed wound healing. While both FAK and NRF2 are independently essential for gastrointestinal wound healing, their mechanistic relationship remains unclear. Emerging evidence suggests that they may be functionally linked through redox-dependent signaling where FAK-mediated ROS production may promote NRF2 activation, while NRF2-driven antioxidant responses maintain conditions necessary for sustained FAK signaling. This coordinated interaction highlights a redox-sensitive feedback mechanism critical for efficient gastrointestinal wound repair. Full article

The mucosal surfaces of the different tracts of the human body occupy a vast interface (around 400 m²), and defense at these sites represents the first line of immune defense. It is at the interface of these surfaces that a cellular and molecular crosstalk among different players is accomplished: the microbiota, the mucosal epithelial, and the immune system. Different lymphocyte populations are present on these surfaces as sentinels, ready to act upon any insult that threatens body homeostasis. One of them are the T-cell-derived intraepithelial lymphocytes (T-IELs), gatekeepers at the mucosal epithelium of the common mucosal system (MALT) (gut, lung, and urogenital tract). These lymphocytes are divided into natural, non-conventional (CD4+/CD8+, TCR αβ, γδ, αα) and induced T-IELs or conventional (CD4+/CD8+ TCR αβ). The most remarkable and distinguishing properties of these innate lymphocyte populations are a triad of attributes: innate, cytotoxic, and memory-protective immune responses. T-IELs are a disregarded population of innate cells, ready to act, for rapid microbial clearance, and an effective support for any mucosal invader. Despite this, T-IELs are an underutilized immunological target that needs further in-depth investigation into their role in inducing fast, rapid clearance of mucosal pathogens, and protective and immune memory (innate and adaptive). The present commentary aims to put into context this emerging potential of T-IELs as immunological targets. Full article

The second stomach compartment (C2) of the dromedary camel (Camelus dromedarius) plays an important role in digestion. However, detailed morphological and histochemical data remain limited. This study aimed to investigate the gross anatomy, histological organization, histometric features, and histochemical distribution of muco-substances in C2. The study was conducted on twenty dromedary camels, including fetuses and adults. Gross anatomical observations were performed on eight fresh and fixed specimens, while histological, histometric, and histochemical analyses were carried out on samples from twelve adult camels using routine and special staining techniques to identify neutral and acidic mucins. C2 was the smallest gastric compartment, located on the right side of the abdominal cavity and partially continuous with C1. Its mucosa formed chambered zones supported by prominent longitudinal muscular bands. Histologically, C2 comprised glandular and non-glandular regions. The glandular mucosa contained gastric pits and branched tubular glands with mucous, chief, and parietal cells, whereas the non-glandular region was lined by keratinized stratified squamous epithelium. Submucosal lymphoid aggregations were observed near the C2–C3 junction. Histometric analysis revealed a markedly developed tunica muscularis. Strong PAS and Alcian blue reactions indicated abundant neutral and acidic mucins. These findings demonstrate that C2 is a structurally specialized compartment supporting digestion, mucosal immune defense, and adaptation to arid environments, clearly distinguishing it from the reticulum of true ruminants. Full article

Background/Objectives: Bitter taste receptors (T2Rs), specifically T2R38, are present in the respiratory epithelium and react with bacterial quorum-sensing molecules to induce an innate immunity response. Although TAS2R38 polymorphisms have been correlated with susceptibility to chronic rhinosinusitis (CRS), they have not yet been explored in odontogenic rhinosinusitis (ORS), a distinct form of CRS with particular microbial and inflammatory features. We aim to establish a proof-of-concept methodology for investigating TAS2R38 genetic variants in ORS using direct maxillary sinus tissue analysis and demonstrate the feasibility of this translational approach. Methods: We conducted a prospective pilot case–control study of 36 ORS patients and 37 controls undergoing septoplasty without sinonasal disease. Maxillary sinus mucosal biopsies were obtained intraoperatively with informed consent. Genomic DNA was extracted using the PureLink Genomic DNA Mini Kit and quantified via NanoDrop spectrophotometry. TAS2R38 haplotypes were determined and classified as taster (PAV/PAV), non-taster (AVI/AVI), or intermediate (PAV/AVI) phenotype. Results: Among fully classifiable canonical TAS2R38 phenotypes (32 ORS patients, 28 controls), distributions were: tasters 12.5% vs. 25.0%, non-tasters 31.3% vs. 25.0%, and intermediate 56.3% vs. 50.0%. AVI/AVI non-taster status was not significantly associated with ORS susceptibility (OR = 1.36, 95% CI: 0.44–4.25; Fisher’s exact p = 0.775). Conclusions: This proof-of-concept study demonstrates that genotyping-grade genomic DNA can be recovered from acutely inflamed maxillary sinus mucosa, validating this substrate for future tissue-based expression, functional, and microbiome analyses not obtainable from peripheral samples; germline genotyping itself does not require sinus tissue. The observed difference in non-taster prevalence (31.3% vs. 25.0%) did not reach statistical significance and is reported descriptively. This directional trend is hypothesis-generating only and, given the limited statistical power, does not constitute evidence for an association. The demonstrated feasibility, together with the established biological rationale, supports an adequately powered confirmatory study and lays the foundation for future investigation of taste receptor genetics in ORS pathogenesis, and potentially personalized therapeutic strategies. Full article

The rumen epithelium of Tibetan sheep plays a critical role in energy metabolism and immune defense; however, its post-transcriptional regulatory mechanisms under high-altitude hypoxia stress remain unclear. In this study, we employed integrated mRNA and miRNA transcriptome sequencing to analyze the adaptive strategies of the rumen epithelium in Tibetan sheep at different altitudes. A total of 2183 differentially expressed genes (DEGs) and 135 differentially expressed miRNAs (DEmiRNAs) were identified. Functional enrichment analysis revealed that DEGs and their target genes were significantly enriched in immune-related pathways such as the NF-κB signaling pathway and cytokine–cytokine receptor interaction, as well as metabolic pathways including oxidative phosphorylation and branched-chain amino acid degradation. Integrated network analysis highlighted key regulatory pairs, including oar-miR-370-3p targeting PCK2 and IL1R2, and novel-miR-781 regulating PIK3R5, suggesting coordinated modulation between mitochondrial homeostasis and immune responses. Specifically, the upregulation of immune genes (CCL19, MADCAM1) and heat shock proteins at TS4500m indicates enhanced mucosal immunity and stress tolerance, while altered expression of metabolic genes reflects a shift in energy substrate utilization. These findings elucidate a complex mRNA-miRNA regulatory network that enables Tibetan sheep to maintain rumen epithelial integrity and energy balance under extreme high-altitude conditions, providing novel insights into the molecular basis of hypoxia adaptation in ruminants. Full article

Background: Eosinophilic chronic rhinosinusitis (ECRS) is characterized by refractory nasal polyps and severely impaired mucociliary clearance (MCC). The molecular mechanisms underlying the modulation of mucociliogenesis following IL-4/13 blockade with dupilumab remain poorly understood, notwithstanding its proven clinical efficacy. Methods: Bulk RNA Barcoding and sequencing (BRB-seq) was performed on nasal polyp tissues collected from healthy controls (n = 6), patients with non-ECRS (n = 8), and patients with ECRS both before and four weeks after dupilumab treatment (n = 9) to identify the early molecular drivers underlying ciliary regeneration. Comprehensive gene-set scoring systems were developed to evaluate multiciliogenesis master regulators, master regulators of core/ciliary planar cell polarity (PCP) and PCP components. Interaction scores for epithelial-derived cytokines—thymic stromal lymphopoietin (TSLP), IL-25, and IL-33—were calculated based on ligand and cognate receptor subunit expression. Results: The ciliary master regulatory hierarchy (e.g., FOXJ1, RFX2/3), PCP components (CELSR1 and the ciliogenesis and planar polarity effector (CPLANE) module: FUZ, INTU, WDPCP), and structural ciliogenesis pathways were robustly restored following IL-4/13 blockade. The TSLP interaction score correlated with global mucosal damage, serving as a trigger for compensatory multiciliogenesis. The pre-treatment IL-33 interaction score emerged as a significant predictor of transcriptomic ciliary recovery (p < 0.05). DNASE1L3—the primary endonuclease for degrading eosinophilic extracellular traps (EETs)—remained persistently downregulated post-treatment. Conclusions: IL-4/13 blockade successfully restores the structural and directional “hardware” of the respiratory epithelium but fails to rectify the enzymatic “software” required for mucus degradation. This “residual molecular scar” may explain the persistent mucus hyperviscosity observed in some ECRS patients even after clinical polyp resolution. Full article

Avibacterium paragallinarum (A. paragallinarum) is the primary causative agent of infectious coryza in chickens. Infection often leads to growth retardation in broilers and a 10% reduction in egg production, reaching over 40% in laying hens. The problem is particularly severe under intensive farming conditions, significantly jeopardizing global poultry health and farming profitability. From a ‘One Health’ perspective, this not only disrupts the stability of the food supply chain, but also increases antibiotic usage due to disease prevention and control needs, thereby aggravating antimicrobial resistance (AMR) and posing a global public health challenge. This review systematically summarizes advances in the pathogenesis of A. paragallinarum and the protective immunity induced by subunit vaccines. It focuses on the infection mechanisms of A. paragallinarum, emphasizing its colonization strategies in the infraorbital sinus and nasal epithelium of chickens, and analyzes the roles of key virulence factors such as hemagglutinin and capsule in adhesion, colonization, and immune evasion. We integrate the tissue-specific pathogenesis of A. paragallinarum with the role of respiratory commensal microbiota in facilitating infection, providing an in-depth analysis of the bacterium’s key immune evasion strategies, thus offering novel insights into host–pathogen-microbiome interactions. Concurrently, to the best of our knowledge, this review provides the first comprehensive overview of current developments in subunit vaccines and their immunoprotective properties, with special attention to limitations in eliciting mucosal immune responses. By delving into the pathogen-host interaction mechanisms, this review aims to inform the optimization of subunit vaccine design and immunization strategies. Ultimately, it seeks to establish a theoretical basis and practical framework for precise control of A. paragallinarum. Full article

HIV is primarily acquired in women at the female genital mucosa through heterosexual contact. Mucosal immune cells reside adjacent to, within, below, and distant from the epithelium that lines the surface of the female genital tract (FGT) mucosa. Innate immune cells play dual roles in HIV acquisition, both poised to rapidly recognize and respond to HIV, but are also capable of promoting HIV infection locally and distantly in the lymph nodes. In this review we emphasize recent human research on the roles of specific innate immune cells in HIV pathogenesis in the FGT, including dendritic cells, macrophages, neutrophils and innate lymphoid cells. We review how FGT mucosal dynamics, including anatomical compartmentalization, menstrual cycle regulation, reproductive history, menopause and chronological aging contribute to tissue conditioning of these cells and changes in HIV susceptibility in women throughout their lives. Full article

The maintenance of gastrointestinal homeostasis relies on a tightly coordinated interplay between the intestinal epithelium, the immune system, and the commensal microbiome. Disruption of this balance underlies inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, and is characterized by chronic, relapsing mucosal inflammation driven by genetic susceptibility, environmental factors, immune dysregulation, and microbial imbalance. Persistent inflammation promotes repeated cycles of epithelial injury and aberrant repair, creating a permissive environment for dysplasia and the development of colitis-associated cancer, most notably colorectal carcinoma. Recent evidence identifies the anti-apoptotic regulator myeloid cell leukemia-1 (Mcl1) as a critical determinant of epithelial integrity and cellular turnover during mucosal stress. Loss or destabilization of Mcl1 disrupts epithelial homeostasis, amplifies inflammatory signaling, and accelerates tumor initiation, whereas its adaptive upregulation in established malignancy promotes tumor cell survival, metabolic fitness, and therapeutic resistance. Thus, Mcl1 functions as a context-dependent molecular switch via restraining malignant transformation during chronic inflammation while supporting tumor progression once neoplasia is established. This functional duality positions Mcl1 as both a biomarker of disease progression and a therapeutically actionable vulnerability. In this review, we synthesize recent advances elucidating how Mcl1 integrates epithelial cell-fate decisions, immune signaling and tumor evolution across the IBD–cancer continuum. We further support these concepts through integrative analyses of multiple transcriptomic datasets comparing normal colonic mucosa with colorectal tumors, and we discuss emerging pharmacological strategies targeting Mcl1 in colitis-associated cancer. Full article

The mammalian intestinal epithelium is a rapid self-renewal tissue in the body, serving as a critical interface between the host and the external environment. Maintaining the intestinal epithelium homeostasis requires precise coordination of cellular processes, including proliferation, migration, differentiation, autophagy, and cell-to-cell interaction. An increasing body of evidence has unveiled circular RNAs (circRNAs) as abundant and stable regulatory molecules that play pivotal roles in the intestinal epithelial biology and are intimately involved in many aspects of gut mucosal pathologies. Unlike linear RNAs, circRNAs form covalently closed loop structures through back-splicing events, conferring remarkable stability and resistance to exonucleolytic degradation. circRNAs regulate the growth of the intestinal mucosa, injury-induced epithelial regeneration, and gut barrier function via diverse mechanisms, including interactions with microRNAs and RNA-binding proteins. Deregulated circRNAs are implicated in the pathogenesis of various gut mucosal disorders such as inflammatory bowel disease and malignancies. In this review, we highlight pathobiological functions and mechanisms of intestinal epithelium-enriched circRNAs, particularly circHIPK3, Cdrlas, and circPABPN1, in the epithelium homeostasis and pathologies and also discuss potential clinical application of circRNAs as diagnostic biomarkers and therapeutic targets in patients with critical diseases. Full article

Chemotherapy-induced mucositis (CIM) is a dose-limiting toxicity of cancer therapy that is mainly associated with mitochondrial dysfunction in epithelial cells. We investigated whether GV1001, a mitochondrial protective peptide from human telomerase reverse transcriptase (hTERT), attenuates 5-fluorouracil (5-FU)-induced mucositis in a murine model. 5-FU induced notable mortality, leukopenia, and mucositis in the gastrointestinal (GI) tract, including tongue, esophagus and small intestine. It promoted epithelial–mesenchymal transition (EMT), nuclear factor kappa-B (NF-κB) activation, systemic and mucosal inflammation, DNA damage, impaired cell proliferation, and apoptosis throughout the GI tract. GV1001 blocked 5-FU–associated mortality, significantly attenuated leukopenia, and notably prevented mucositis. GV1001 also suppressed 5-FU-induced DNA damage, EMT, loss of proliferative capacity, apoptosis, and NF-κB activation in mucosal epithelium. In normal human keratinocytes, 5-FU inhibited the cell proliferation, disrupted mitochondrial function, as evidenced by reduced mitochondrial membrane potential, increased reactive oxygen species (ROS) production, impaired electron transport chain (ETC) complex integrity, decreased ATP synthesis, and cytochrome c release into the cytosol. GV1001 markedly mitigated these 5-FU-induced mitochondrial defects. Taken together, GV1001 mitigates CIM by most likely preserving mitochondrial integrity and function, supporting its potential as a strategy to prevent cancer chemotherapy-associated mucosal injury in patients. Full article