Search Results (295)

Neuroprotection represents a promising approach for mitigating retinal degeneration. Cord blood serum (CBS), rich in trophic factors such as the brain-derived neurotrophic factor (BDNF), has shown therapeutic potential for ocular surface diseases; however, its role in retinal neuroprotection remains underexplored. This study evaluates the protective effects of CBS on retinal pigment epithelium (ARPE-19) and photoreceptor-like (661W) cells exposed to oxidative stress. Cells were cultured in media supplemented with fetal bovine serum (FBS) or CBS with either high (CBS-H) or low (CBS-L) BDNF content. Oxidative stress was induced using hydrogen peroxide (H₂O₂), and cell viability was measured via an MTS assay. ZO-1 expression was analyzed in ARPE-19 cells to assess tight junction integrity, while mitochondrial function in 661W cells was examined using MitoRed staining. TrkB receptor involvement was investigated using the inhibitor K252a and Western blot analysis. CBS significantly improved cell viability under oxidative conditions. CBS-H increased ZO-1 expression in ARPE-19 cells, indicating preserved epithelial integrity. In 661W cells, CBS maintained mitochondrial integrity and enhanced TrkB phosphorylation, while TrkB inhibition reduced its protective effect. These findings indicate that CBS confers neuroprotection through BDNF-TrkB signaling together with other trophic factors, supporting its potential as a multifactorial therapeutic strategy for retinal degeneration that deserves further exploration. Full article

During the COVID-19 pandemic, the prevalence of death in men was higher than in women. Using transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2), we demonstrated that SARS-CoV-2 infects Leydig cells and uses its steroidogenic machinery for replication. This study investigates the impact of SARS-CoV-2 in the seminiferous epithelium of K18-hACE2 mice, focusing on the immune response, junctional proteins, and spermatogenesis. The seminiferous tubules (STs) and epithelial (EA) areas were measured. The number of Sertoli cells (SCs), spermatocytes, and damaged ST was quantified. Ultrastructural analysis was performed under transmission electron microscopy. Angiotensin II levels and immunolocalization of hACE2, spike, and nucleocapsid were evaluated. TUNEL and immunoreactions for Ki-67, TNF-α, INF-γ, iNOS, NF-κB, and Conexin-43 were performed and correlated with Jam-α, Stat1, Stat3, and iNOS expressions. hACE2, spike, and nucleocapsid immunolabeling were detected in the epithelium along with high angiotensin II levels in the infected mice. The infection caused a significant reduction in ST, EA, spermatocytes, SCs, Ki-67+ cells, Cx43 immunoexpression, and Jam-a expression. In the epithelium, TNF-α, IFN-γ, iNOS, and nuclear NF-κB immunolabeling increased along with Stat1 upregulation. These findings, combined with the increased epithelial hACE2 and high angiotensin II levels, confirm epithelial responsiveness to the infection and explain the spermatogenic failure and impaired junctional proteins. The presence of viral particles, increased TNF-α immunolabeling, and apoptotic features in Sertoli cells suggests that these sustentacular cells are targets for viral infection in the epithelium, and, due to their extensive projections and ability to phagocytize dying infected germ cells, they may disseminate the viruses throughout the epithelium. Full article

The cornea maintains transparency by preserving immune and (lymph)angiogenic privilege through active suppression of inflammation and vascular invasion, a process centrally regulated by limbal epithelial stem cells (LESCs) located at the corneoscleral junction. Beyond renewing the corneal epithelium, LESCs maintain immune and vascular balance via extracellular matrix interactions and paracrine signalling, exerting predominantly anti-inflammatory and anti-(lymph)angiogenic effects in vivo. Disruption of the limbal niche by trauma, UV exposure, or genetic disorders such as aniridia leads to limbal stem cell deficiency (LSCD), chronic inflammation, loss of corneal avascularity, and vision loss. The identification of ABCB5 as a key LESC marker has clarified functional limbal subsets, highlighting ABCB5⁺ epithelial cells as mediators of repair, remodelling, and immune suppression, and positioning them as promising therapeutic targets for treatments that restore both epithelial integrity and corneal immune privilege. Full article

A limited period of endometrial receptivity is defined by molecular interactions between the embryo and maternal tissues, which are crucial for successful implantation. The results of clinical studies assessing intrauterine human chorionic gonadotropin (hCG) as an endometrial priming agent in in vitro fertilisation (IVF) have been inconsistent, markedly affected by dose, timing, and cycle context. This narrative review summarises molecular data demonstrating that hCG modulates immunological, stromal, endothelial, and epithelial compartments in a coordinated manner, affecting essential endometrial processes. hCG promotes adhesion competence and proliferation in the epithelium via a microRNA-regulated signalling axis (miR-126-3p–PIK3R2–PI3K/Akt). Intrauterine hCG promotes controlled apposition and invasion at the vascular interface by selectively strengthening endothelial junctional cohesion via VE-cadherin and CD146, without promoting angiogenesis. hCG collaborates with ERK/mTOR signalling to regulate autophagy and apoptosis, alters steroid–receptor networks in the stroma, initiates early decidual and survival markers (ACTA2, NOTCH1, complement C3), and enhances stress resistance. hCG modifies the immunological milieu by enhancing the activity of regulatory T cells and altering the distribution of uterine natural killer cells. This facilitates immunological tolerance and the remodelling of spiral arteries. These pleiotropic effects together enhance biomarkers and provide a scientific justification for context-dependent clinical responses, including patient-chosen, directed methods for the delivery of intrauterine hCG during IVF. Full article

Inherited retinal degenerations (IRDs), driven by pathogenic mutations, often involve primary dysfunction of the retinal pigment epithelium (RPE)—a pathogenic feature shared with atrophic age-related macular degeneration (aAMD), despite aAMD’s multifactorial etiology. Prominin-1 (Prom1), traditionally linked to photoreceptor pathology, has an unclear role in RPE homeostasis. We assessed Prom1 expression in C57BL/6J mouse retina sections and RPE flat mounts using immunohistochemistry and generated Prom1-knockout (KO) mouse RPE cells via CRISPR/Cas9. Bulk RNA sequencing with DESeq2 and gene set enrichment analysis (GSEA) revealed Prom1-regulated pathways. Prom1-KO cells exhibited upregulation of Grem1, Slc7a11, Serpine2, Il1r1, and IL33 and downregulation of Ablim1, Cldn2, IGFBP-2, BMP3, and OGN. Hallmark pathway interrogation identified reduced expression of PINK1 (mitophagy) and MerTK (phagocytosis), implicating defects in mitochondrial quality control and outer segment clearance. Enrichment analysis revealed activation of E2F/MYC targets, mTORC1 signaling, oxidative phosphorylation, and TNFα/NF-κB signaling, alongside suppression of apical junctions, bile acid metabolism, and Epithelial-Mesenchymal Transition (EMT) pathways. These findings suggest Prom1 safeguards RPE integrity by modulating stress responses, mitochondrial turnover, phagocytosis, metabolism, and junctional stability. Our study uncovers Prom1-dependent signaling networks, providing mechanistic insights into RPE degeneration relevant to both IRD and aAMD, and highlights potential therapeutic targets for preserving retinal health. Full article

Gastrointestinal cancers, including gastric, gastroesophageal junction, pancreatic, and biliary tract cancers, remain associated with poor outcomes due to late diagnosis and limited effective treatment options. Claudin-18.2 (CLDN18.2), a tight junction protein primarily found in the gastric epithelium and ectopically expressed in gastrointestinal tumors, has emerged as a promising therapeutic target across these diseases. This narrative review expands on existing discussions surrounding CLDN18.2-directed therapy in gastric and gastroesophageal cancer and provides a comprehensive, updated analysis of the rapidly evolving therapeutic landscape across multiple gastrointestinal malignancies, including pancreatic and biliary tract cancers. We summarize key developments following the approval of the monoclonal antibody zolbetuximab and critically evaluate emerging modalities, including bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cell therapies, highlighting differences in mechanisms of action, efficacy, toxicity profiles, and mitigation strategies. We also discuss the clinical relevance of CLDN18.2 and PD-L1 co-expression, the rationale for pairing CLDN18.2-targeted therapy with immune checkpoint inhibitors, and early data supporting combination approaches. Additionally, we examine tumor heterogeneity, biomarker challenges, and emerging resistance mechanisms, alongside strategies to overcome them. Finally, we identify current limitations in the field, including inconsistent CLDN18.2 testing criteria, and outline prioritized future directions to optimize integration of CLDN18.2-directed therapies across gastrointestinal cancers. By looking beyond zolbetuximab and incorporating cross-platform comparison, immuno-oncology considerations, and multi-tumor context, this review provides a broad and forward-looking framework to guide clinical application and next-generation research in CLDN18.2-targeted therapy. Full article

The intestinal epithelium constitutes a critical barrier that protects the host from luminal toxins. Persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls, are ubiquitous aryl hydrocarbon receptor (AhR) ligands. However, their effects on intestinal barrier integrity remain poorly understood. We examined representative POPs in vitro (using human Caco-2 monolayers) and in vivo (using a mouse jejunal loop model). Measurements of transepithelial electrical resistance, fluorescein isothiocyanate–dextran permeability, and cytotoxicity revealed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impaired barrier function at non-cytotoxic concentrations. This effect was accompanied by increased ethoxyresorufin-O-deethylase activity and subsequently reversed by the AhR antagonist CH223191, indicating AhR dependence. Mechanistically, TCDD suppressed claudin-1, claudin-4, and zonula occludens-1 expression while upregulating the transcription factor Slug, consistent with junctional remodeling. In vivo, TCDD enhanced systemic dextran leakage and reduced claudin-4 expression in jejunal epithelia. These findings identify intestinal barrier disruption as a sensitive toxicological endpoint of POP exposure and provide mechanistic insight into the link between environmental pollutants and gastrointestinal dysfunction. Full article

Understanding asthma’s endotypes is key to advancing precision medicine. Using omics techniques on sputum, bronchial epithelium, and blood have revealed T2 and non-T2 asthma, each which have been further categorized into T2 and non-T2 subgroups. Despite advances in understanding asthma’s molecular complexity, many questions remain. Future research could either enhance current multiomics approaches with sophisticated bioinformatics or integrate hypothesis-driven research. It is now widely accepted that the airway epithelium starts and regulates the inflammatory cascade in asthma. If asthma originates in the altered epithelium, concentrating research on epithelial dysfunction is logical. This approach is likely more straightforward than analyzing the multitude of genes affected by the inflammatory cascade triggered by this disturbed airway epithelium. The airway epithelium comprises various cell types, including basal cells, club cells, ciliated cells, goblet cells, pulmonary neuroendocrine cells, tuft cells, and pulmonary ionocytes, which are connected by junctional complexes including tight junctions, adherens junctions, gap junctions, and desmosomes. The healthy airway epithelium helps support homeostasis, defend against threats, and regulate immunity through innate and adaptive systems. Chronic airway epithelial barrier dysfunction can instigate and propagate excessive immune responses. Knowing the cellular makeup and differentiation of the airway epithelium is vital for creating treatments to restore airway integrity in established asthma. A new consensus highlights focusing research on airway epithelial dysfunction as the main driver of inflammation, marking the start of the “epithelium era” in asthma research. Full article

Therapeutic peptides have gained significant attention due to their high specificity, potency, and safety profiles in treating various diseases. However, their clinical application via the oral route remains challenging. Peptides are inherently unstable in the gastrointestinal environment, where they are rapidly degraded by proteolytic enzymes and acidic pH, leading to poor bioavailability. Additionally, their large molecular size and hydrophilicity restrict passive diffusion across the epithelial barriers of the gastrointestinal tract. These limitations have traditionally necessitated parenteral administration, which reduces patient compliance and convenience. The oral cavity, comprising the buccal and sublingual mucosa, offers a promising alternative for peptide delivery. Its rich vascularization allows for rapid systemic absorption while bypassing hepatic first-pass metabolism. Furthermore, the mucosal surface provides a relatively permeable and accessible site for drug administration. However, the oral cavities also present significant barriers: the mucosal epithelium limits permeability, the presence of saliva causes rapid clearance, and enzymes in saliva contribute to peptide degradation. Therefore, innovative strategies are essential to enhance peptide stability, retention, and permeation in this environment. Nanoparticle-based delivery systems, including lipid-based carriers such as liposomes and niosomes, as well as polymeric nanoparticles like chitosan and PLGA, offer promising solutions. These nanocarriers protect peptides from enzymatic degradation, enhance mucoadhesion to prolong residence time, and facilitate controlled release. Their size and surface properties can be engineered to improve mucosal penetration, including through receptor-mediated endocytosis or by transiently opening tight junctions. Among these, niosomes have shown high encapsulation efficiency and sustained release potential, making them particularly suitable for oral peptide delivery. Despite advances, challenges remain in translating these technologies clinically, including ensuring biocompatibility, scalable manufacturing, and patient acceptance. Nevertheless, the oral cavity’s accessibility, combined with nanotechnological innovations, offers a compelling platform for personalized, non-invasive peptide therapies that could significantly improve treatment outcomes and patient quality of life. Full article

This study aimed to review the effects of simple carbohydrates (SCs), fibre, proteins, fats, and alcoholic beverages on human gastrointestinal tract (GIT) morphology. Additional objectives included describing normal human GIT morphology, the mentioned dietary components, and their connection to GIT pathologies. An extensive literature review was conducted using PubMed, Scopus, ScienceDirect, and Google Scholar. This study revealed that excessive SC intake can increase intestinal permeability, modify gut microbiota, and cause tooth decay. Dietary fibre, through microbiota modulation, can enhance epithelium proliferation, improve intestinal barrier integrity, and prevent or manage GIT pathologies. Excessive protein consumption can decrease tight junction protein expression and increase inflammation, while insufficient intake can result in villi atrophy and increased permeability. A high-saturated-fat diet can increase intestinal permeability, increase inflammation, and promote gut dysbiosis, whereas omega-3 fatty acids can reduce inflammation and improve epithelial integrity. Immoderate alcohol use damages the GIT epithelium, causing inflammation and increasing the risk of cancer. The reviewed dietary components notably impact GIT morphology and are linked to various GIT pathologies. These findings highlight a balanced diet’s substantial role in preserving GIT health. Full article

Mycotoxins are toxic secondary metabolites produced by filamentous fungi that contaminate agricultural commodities, posing risks to food safety, animal productivity, and human health. The gastrointestinal tract is the first and most critical site of exposure, where the intestinal epithelium functions as both a physical and immunological barrier against luminal toxins and pathogens. While extensive research has demonstrated that mycotoxins disrupt epithelial integrity through tight junction impairment, oxidative stress, apoptosis, and inflammation, their effects on the intestinal stem cell (ISC) compartment and epithelial regeneration remain insufficiently understood. This review integrates recent findings from in vivo, cell culture, and advanced 3D intestinal organoid and gut-on-chip models to elucidate how mycotoxins such as deoxynivalenol and zearalenone impair ISC proliferation, alter Wnt/Notch signaling, and compromise mucosal repair. We also discuss dose relevance, species differences, and the modulatory roles of the microbiome and short-chain fatty acids, as well as emerging evidence of additive or synergistic toxicity under co-exposure conditions. By bridging well-established mechanisms of barrier disruption with the emerging concept of ISC-driven regenerative failure, this review identifies a critical knowledge gap in mycotoxin toxicology and highlights the need for integrative models that link epithelial damage to impaired regeneration. Collectively, these insights advance understanding of mycotoxin-induced intestinal dysfunction and provide a foundation for developing nutritional, microbial, and pharmacological strategies to preserve gut integrity and repair. Full article

Background/Objectives: Traumatic brain injury (TBI) disrupts both the intestinal epithelium and blood–brain barrier (BBB), contributing to oxidative stress, neuroinflammation, and behavioral impairments. Vitis vinifera leaf (VVL) extract possesses antioxidant and anti-inflammatory properties, but its protective effects on the brain–gut axis following TBI remain unclear. This study aimed to evaluate whether VVL supplementation preserves barrier integrity and improves neurobehavioral outcomes after TBI. Methods: A murine model of TBI was used, with animals receiving daily oral supplementation of the VVL extract. Neurobehavioral performance was assessed through behavioral testing, while histopathological examinations, biochemical assays, and gene expression profiling were performed to evaluate neuronal and intestinal integrity, antioxidant defense, and inflammatory responses. Results: VVL supplementation significantly alleviated anxiety- and depression-like behaviors and preserved the structural integrity of neuronal and intestinal tissues. Antioxidant defense mechanisms were strengthened, as shown by increased catalase and superoxide dismutase activities, together with upregulation of Nrf2 and HO-1 expression. Tight junction proteins, including ZO-1 and occludin, were upregulated in both brain and gut tissues, reflecting improved barrier integrity. Furthermore, VVL markedly reduced pro-inflammatory cytokine expression. Conclusions: VVL extract confers dual protection of the gut and brain barriers after TBI by enhancing endogenous antioxidant defenses, maintaining tight junction integrity, and suppressing inflammation. These findings suggest that VVL may represent a natural therapeutic strategy to mitigate oxidative stress, neuroinflammation, and behavioral dysfunctions associated with TBI. Full article

Background/Objectives: Obesity and dysglycemia are increasingly associated with intestinal barrier dysfunction and alterations in gut microbiota. Intestinal hyperpermeability is emerging as a therapeutic target in metabolic disorders, but human data integrating barrier biomarkers, epithelial morphology, and microbial composition remain scarce. Methods: Forty-six adults (82.6% female; 38.3 ± 7.8 years) were stratified into lean normoglycemic controls (CON), individuals with obesity and normoglycemia (NOB), and those with obesity and dysglycemia (DOB). Biochemical/inflammatory biomarkers, such as lipopolysaccharide (LPS) and LPS-binding protein (LBP), were measured. Duodenal biopsies were obtained by upper digestive videoendoscopy. Histomorphometry, expression of junctional and cytoskeletal proteins, and enzymatic activity of the duodenal epithelium were used as markers of intestinal permeability. Fecal microbiota composition (FMC) was analyzed by amplifying the V4 region of the 16S rRNA gene, which was sequenced using next-generation sequencing technology. Results: Duodenal histomorphometry did not differ across groups. Intestinal alkaline phosphatase (IAP) was significantly lower in DOB compared to CON. LPS correlated positively with fat mass, and LBP with the waist-to-hip ratio. The villus-to-crypt ratio correlated negatively with BMI, while IAP correlated inversely with fasting glucose and HbA1c. β-actin expression was inversely associated with BMI, glucose, insulin, and HOMA-IR. Microbiota diversity indices were similar between groups, although specific taxa, particularly within the Clostridiales order, were reduced in dysglycemia. Conclusions: Reduced IAP activity and consistent correlations between barrier biomarkers and metabolic parameters highlight intestinal barrier dysfunction as a relevant feature of obesity and dysglycemia. Subtle microbiota alterations further support a link between gut ecology and metabolic control. These findings underscore the intestinal barrier as a promising therapeutic target in metabolic disorders. Full article

This study aimed to investigate the effects of Pogostemon cablin essential oil (PEO) on rumen development in heat-stressed beef cattle. Eighteen male Jingjiang cattle were randomly assigned to two groups and fed a diet containing PEO at 0 mg/kg (Control) and 50 mg/kg in the feed concentrate (n = 9 per group). The rumen fluid samples had lower ammonia nitrogen and higher cellulase activity, propionate and total volatile fatty acids concentrations in the 50 mg/kg PEO group. Compared with the control group, 50 mg/kg dietary supplementation with PEO increased crude protein and neutral detergent fiber digestibility. Additionally, the ruminal tissue papilla height, the papilla surface area, and the activities of glutathione peroxidase, total superoxide dismutase, and total antioxidant capacity were also higher, while the malondialdehyde content was lower for the heat-stressed cattle in the 50 mg/kg PEO group. Furthermore, PEO increased the average optical density values and mRNA expression of zonula occludens-1 (ZO-1) and occludin (p < 0.05). Transcriptomics analysis of the rumen epithelium showed that PEO upregulated the expression levels of genes related to tight junction proteins and the DNA replication/repair pathways, while it downregulated pro-apoptotic genes. In summary, dietary PEO supplementation improved nutrient digestibility, enhanced rumen antioxidant capacity, and promoted the repair of damaged rumen epithelium in heat-stressed cattle, indicating that PEO exerts a prominent protective effect on rumen function. Full article

Berberine (BBR), a benzylisoquinoline alkaloid isolated from Chinese herb Coptis chinensis, has been widely used clinically to treat intestinal infectious diseases. Recently, it has been found to have multiple pharmacological effects, including anti-inflammatory activity and immune effects in inflammatory bowel disease (IBD). However, its exact targets remain to be elucidated. In this study, we used a mouse intestinal organoid–macrophage co-culture model to investigate the anti-inflammatory effects and immune effects of BBR. Our findings demonstrated that lipopolysaccharide (LPS) induced more robust inflammatory responses and epithelium damage in the co-culture system compared to the organoid alone. BBR effectively attenuated inflammation and restored epithelial barrier integrity by suppressing M1 macrophage polarisation and infiltration, alongside upregulating the expression and organisation of tight junction protein zonula occludens-1 (ZO-1). RNA sequencing and proteomic analysis revealed that BBR disrupted organoid–macrophage interaction by inhibiting chemokine (e.g., C-X-C motif chemokine ligand 1 (CXCL1) and macrophage migration inhibitory factor (MIF)) release from epithelial cells, thereby reducing macrophage recruitment. Collectively, our study establishes the organoid–macrophage co-culture system as a more physiologically relevant model for studying epithelial–immune interactions and elucidates the multi-target mechanism of BBR, which concurrently modulates epithelial cells, macrophages, and their crosstalk. These findings lay the foundation for further exploration of the therapeutic potential of BBR in inflammatory bowel disease and the development of targeted therapies that regulate cell interactions. Full article