Although salivary glands are highly vascularized, the microvascular endothelial barrier has only recently emerged as a pivotal determinant of glandular homeostasis and disease. This review synthesizes current understanding of the salivary gland endothelial barrier, with particular emphasis on the regulation of tight junctions (TJs). Structurally, the barrier comprises endothelial cells interconnected by TJs and adherens junctions, supported by a basement membrane and pericytes. Among TJ components, claudin-5 serves as a key endothelial-specific regulator of paracellular permeability, and is dynamically modulated by biochemical and mechanical stimuli during saliva secretion. Cholinergic, adrenergic, and neuropeptide signaling pathways coordinate to fine-tune endothelial permeability to meet the fluctuating secretory demands. Conversely, under pathological conditions, such as Sjögren's syndrome, radiation-induced injury, diabetes mellitus, fibrotic diseases, and salivary gland tumors, the integrity of the endothelial TJ complex is impaired. These pathologies are characterized by aberrant TJ expression, mislocalization, and signaling-mediated junctional disassembly, which trigger vascular leakage and immune cell infiltration-two key processes that act as primary drivers of glandular dysfunction. Collectively, these findings enrich our understanding of the microvascular mechanisms that link endothelial barrier function to salivation, and highlight that the restoration of junctional integrity is a promising therapeutic strategy for salivary gland diseases.

Background Disruption of circadian regulation and gut microbial homeostasis is a hallmark of metabolic dysfunction associated with steatotic liver disease (MASLD). Nuclear factor interleukin 3 (Nfil3) integrates circadian and immune signaling; however, how Nfil3 interfaces with microbiota-associated metabolic cues in MASLD remains incompletely understood. We investigated the role of Nfil3 in linking microbial functional states to hepatic metabolic and immune responses under high-fat diet (HFD) stress and assessed the modulatory impact of probiotic VSL#3 intervention. Methods We integrated exploratory human peripheral blood mononuclear cell (PBMC) transcriptomic profiling with genetic Nfil3 deletion and probiotic VSL#3 supplementation in HFD-fed mice. Experimental assessments included liver histopathology, metabolic phenotyping, immune flow cytometry, gut epithelial barrier analysis, 16S rRNA microbiome profiling with predictive functional inference, and RT-PCR. Results Exploratory PBMC transcriptomic analysis of obese individuals suggested that NFIL3 may function as a candidate transcriptional node associated with circadian-related genes and short-chain fatty acid (SCFA) sensing receptors in inflammatory signaling pathways. In mice, HFD feeding was associated with increased Nfil3 expression, hepatic steatosis, metabolic dysfunction, immune cell expansion, and impaired intestinal epithelial barrier integrity. Probiotic VSL#3 supplementation mitigated several HFD-associated phenotypes, including weight gain, glucose intolerance, dyslipidemia, transaminase elevation, hepatic lipid accumulation, and gut epithelial permeability, while partially normalizing intrahepatic immune cell composition. Nfil3-deficient mice displayed attenuated responses to several HFD-induced metabolic and inflammatory alterations, with partial phenotypic overlap with probiotic-treated wild-type (WT) mice. Microbiome analyses showed that VSL#3 enriched SCFA- and mucin-associated taxa while suppressing endotoxin-associated bacteria (Desulfovibrionaceae, Romboutsia). Predictive functional profiling suggested restoration of microbial pathways related to amino acid, redox, and energy metabolism, alongside reduced representation of lipopolysaccharide and toxin biosynthesis pathways. Conclusions These findings support a role for Nfil3 as a regulatory node linking microbial functional potential with immune and metabolic responses in MASLD. Although preclinical in nature, this work provides a mechanistic framework that may inform future translational investigations into how microbiota-associated metabolic reprogramming influences host immune-metabolic homeostasis. Further circadian-resolved and metabolite-level studies, together with human interventional validation, will be required to determine the clinical relevance of the microbiota-Nfil3 axis.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem metabolic disorder accompanied by extrahepatic complications, including renal dysfunction. High-fat diet (HFD) and choline-deficient, L-amino acid–defined high-fat diet (CDAHFD) are widely used experimental models of MASLD; however, their comparative effects on hepatic and renal pathology, immune cell composition, and gut microbial profiles remain incompletely characterized. Male C57BL/6 mice were fed with a normal chow diet (NCD), HFD (16 weeks), or CDAHFD (8 weeks). Metabolic profiles, hepatic and renal histopathology, biochemical indices, and flow-cytometric immune cell analyses were performed. Parallel 16S rRNA sequencing and STAMP-based Welch’s t-tests were used to identify diet-specific alterations in microbial communities and functional pathways. Both dietary interventions induced steatosis and systemic metabolic disturbances, but CDAHFD provoked more severe hepatic inflammation, collagen deposition, and renal dysfunction. HFD-fed mice exhibited gradual hyperglycemia, dyslipidemia, and glomerular hypertrophy, whereas CDAHFD-fed mice developed acute hepatocellular injury accompanied by elevated blood urea nitrogen (BUN) and creatinine. Flow cytometric analysis revealed diet-specific differences in renal immune cell composition, with HFD favoring macrophage-dominant profiles and CDAHFD associated with increased inflammatory monocyte, dendritic cell, and T-cell proportions. Gut microbiota profiling demonstrated distinct compositional signatures between diets: HFD feeding was associated with increased relative abundance of Dubosiella newyorkensis and Faecalibaculum rodentium, whereas CDAHFD feeding was characterized by enrichment of Romboutsia ilealis and Kineothrix alysoides, accompanied by a pronounced reduction in microbial diversity. Distinct nutrient compositions elicited divergent immunometabolic and microbial responses across the gut–liver–kidney axis. HFD and CDAHFD produce disparate hepatic, renal, immune, and microbial phenotypes in mice, indicating unique metabolic injury mechanisms rather than synchronized disease stages. Although mechanistic inter-organ communication was not directly assessed, this comparative framework highlights the importance of dietary composition and injury kinetics when interpreting multi-organ outcomes in experimental MASLD models.

This chapter explores the complex interplay between gut microbiota (GM), immune checkpoint inhibitors, and HCC. HCC, the most common form of primary liver cancer, often arises from chronic liver diseases influenced by the gut-liver axis. Dysbiosis of the GM—characterized by imbalances in GM populations—has been linked to liver inflammation, fibrosis, and tumor progression. This chapter highlights the critical role GM play in modulating immune responses, particularly in the efficacy of ICIs. Beneficial bacteria such as Akkermansia muciniphila and Bifidobacterium have been shown to enhance ICI effectiveness, while microbial imbalances can lead to poor treatment outcomes. Emerging therapeutic strategies, including fecal microbiota transplantation (FMT), probiotics, and prebiotics, offer promising approaches to restoring GM balance and improving ICI responses in HCC patients. The chapter also discusses future research directions, emphasizing the need for personalized GM-based therapies and large-scale clinical trials to validate these findings. By harnessing the GM, there is potential to significantly enhance the efficacy of immunotherapy for HCC, offering new hope for patients facing this aggressive cancer.

Abstract A high-fat diet (HFD) alters the gut microbiota (GM), impairs metabolic efficiency, and increases gut permeability and inflammation. Obesity and insulin resistance are associated with GM dysbiosis. The GM is strongly associated with metabolic disorders and fatty liver disease. The co-chaperone protein FK506-binding protein-5 (FKBP5) regulates several vital cellular processes. Although FKBP5 has been implicated in stress-related disorders, it has not been directly linked to HFD-induced metabolic fatty liver disease. This study aimed to elucidate how FK506 binding protein 5 impairment affects the GM in HFD-induced metabolic dysfunction–associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease (MASLD). Wild-type and FKBP5-knockout (FKKO) mice were fed a normal chow diet or a high-fat diet for 16 weeks. Mouse GM was examined using 16 S rRNA metagenomic analysis. The number of gut-liver immune cells was measured using flow cytometry. HFD-induced hepatic steatosis and inflammation were prevented in FKBP5-deficient mice. FKKO animals showed higher butyric acid levels and GM resistance to diet-induced obesity alterations according to 16 S ribosomal rRNA gene analysis and displayed an HFD-specific gut-liver immunological response that maintained gut barrier failure and mucosal immunity, which are important for GM homeostasis. FKBP5 helps the GM address inadequate immunological responses, including lower gut and liver CD11b+Ly6C+ monocytes and neutrophils, and protects against obesity by improving the GM response to HFD-induced MASLD. FKBP5 protects against HFD-induced MASLD through metabolic coordination between the gut barrier and intrahepatic immunity.

BACKGROUND:Excessive exposure to blue light (BL) from light-emitting diodes (LEDs) induces oxidative stress and photoreceptor degeneration, contributing to retinal damage. Abelmoschus manihot flower extract (AME), rich in flavonoids, possesses antioxidant and anti-inflammatory properties; however, its protective effects on the retina have not been fully elucidated. METHODS:We investigated the protective effects of AME in vivo using a BL-induced retinal damage model in C57BL/6J mice and in vitro using hydrogen peroxide (H2O2)-induced oxidative stress in 661W photoreceptor cells. Retinal morphology, synaptic integrity, and oxidative stress markers were assessed through histology, immunohistochemistry, and transmission electron microscopy. In vitro analyses included cell viability assays, TUNEL staining, reactive oxygen species (ROS) measurement, and evaluation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and localization. RESULTS:AME pretreatment preserved the structural integrity of the photoreceptor layer, maintained outer segment and synaptic ribbon architecture, and reduced 8-hydroxy-2'-deoxyguanosine (8-OHdG) accumulation in BL-exposed retinas. In 661W cells, AME enhanced cell viability, decreased apoptosis, and attenuated ROS production. Furthermore, AME upregulated Nrf2 expression and promoted its nuclear translocation, suggesting activation of the antioxidant response pathway. CONCLUSIONS:AME exerts protective effects against BL-induced retinal degeneration and oxidative stress-induced photoreceptor apoptosis, potentially through activation of the Nrf2 pathway. These findings highlight the therapeutic potential of AME in preventing or mitigating retinal damage associated with oxidative stress.

Background: Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods: SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results: SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion: SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.