Search Results (342)

Background: Chronic kidney disease (CKD) represents a state of persistent, sterile low-grade inflammation in which sustained innate immune activation accelerates renal decline and cardiovascular complications. Diet-induced gut dysbiosis and intestinal barrier dysfunction lower mucosal immune tolerance, promote metabolic endotoxemia, and position the gut as an upstream modulator of systemic inflammatory signaling along the gut–kidney axis. Scope: Most studies address microbiota-derived metabolites, food-derived bioactive peptides, or omega-3 fatty acids separately. This review integrates evidence across these domains and examines their convergent actions on epithelial barrier integrity, immune polarization, oxidative-inflammatory stress, and inflammasome-dependent pathways relevant to CKD progression. Key mechanisms: CKD-associated dysbiosis is characterized by reduced short-chain fatty acid (SCFA) production and increased generation and accumulation of uremic toxins and co-metabolites, including indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, and altered bile acids. Reduced SCFA availability weakens tight junction-dependent barrier function and regulatory immune programs, favoring Th17-skewed inflammation and endotoxin translocation. Bioactive peptides modulate inflammatory mediator networks and barrier-related pathways through effects on NF-κB/MAPK signaling and redox balance, while omega-3 fatty acids and specialized pro-resolving mediators support resolution-phase immune responses. Across these modalities, shared control points include barrier integrity, metabolic endotoxemia, oxidative stress, and NLRP3 inflammasome activation. Conclusions: Although evidence remains heterogeneous and largely preclinical, combined nutritional modulation targeting these convergent pathways may offer greater immunomodulatory benefit than isolated interventions. Future multi-omics-guided, factorial trials are required to define responder phenotypes and translate precision immunonutrition strategies into clinical CKD care. Full article

Bluetongue virus (BTV) infects various ruminant species, posing significant threats to animal health and causing substantial economic losses to the livestock industry. Ovine type II alveolar epithelial cells (OAECIIs) play crucial roles in maintaining pulmonary structural integrity and modulating immune responses. Their dysfunction is closely associated with lung disease pathogenesis, making them important therapeutic targets. However, OAECIIs’ immunoregulatory functions and early response mechanisms during BTV infection remain unclear. To address this, we analyzed transcriptomic changes in OAECIIs following BTV-1 infection. RNA-seq revealed 1047 and 852 differentially expressed genes (DEGs) at 8 and 12 h post-infection (hpi), respectively, compared to uninfected controls. Bioinformatics analysis showed significant upregulation of nucleic acid-sensing receptors, interferon-stimulating factors, inflammatory mediators, and cytokines during early infection, mediated primarily through type I interferon signaling, TNF signaling, and cytosolic DNA-sensing pathways. We identified MAD5, ZNFX1, cGAS, OAS, PKR and ZBP1 as key pattern recognition receptors in OAECIIs during BTV infection. The IFN-β, MX1/2, RSAD2 and PLSCR1 pathways mediated antiviral responses, while IL-15, CXCL10, CCL2 triggered inflammatory responses, collectively causing structural alterations through AQP1/9 and tight junction protein modulation. These findings provide critical insights into early antiviral mechanisms and cellular structural changes in OAECIIs during BTV infection, establishing a foundation for understanding pneumonia pathogenesis and developing targeted BTV therapies. Full article

Peptide-based biomaterials have emerged as versatile tools for pharmaceutical drug delivery due to their biocompatibility and tunable sequences, yet a comprehensive overview of their categories, mechanisms, and optimization strategies remains lacking to guide clinical translation. This review systematically collates advances in peptide-based biomaterials, covering peptide excipients (cell penetrating peptides, tight junction modulating peptides, and peptide surfactants/stabilizers), self-assembling peptides (peptide-based nanospheres, cyclic peptide nanotubes, nanovesicles and micelles, peptide-based hydrogels and depots), and peptide linkers (for antibody drug-conjugates, peptide drug-conjugates, and prodrugs). We also dissect sequence-based optimization strategies, including rational design and biophysical optimization (cyclization, stapling, D-amino acid incorporation), functional motif integration, and combinatorial discovery with AI assistance, with examples spanning marketed drugs and research-stage candidates. The review reveals that cell-penetrating peptides enable efficient intracellular payload delivery via direct penetration or endocytosis; self-assembling peptides form diverse nanostructures for controlled release; and peptide linkers achieve site-specific drug release by responding to tumor-associated enzymes or pH cues, while sequence optimization enhances stability and targeting. Peptide-based biomaterials offer precise, biocompatible and tunable solutions for drug delivery, future advancements relying on AI-driven design and multi-functional modification will accelerate their transition from basic research to clinical application. Full article

Background: Aging exerts a progressive and multifaceted impact on the microcirculatory system, undermining the structural and molecular integrity that sustains endothelial stability across both peripheral and cerebral vascular territories. A sustained shift toward oxidative imbalance, chronic low-grade inflammation, and progressive endothelial exhaustion converges to destabilize microvascular networks, linking peripheral artery disease (PAD) with heightened susceptibility to cerebral microvascular dysfunction and neurovascular decline. As redox homeostasis deteriorates, endothelial cells progressively lose barrier-selective properties, intercellular communication with pericytes weakens, and pro-thrombotic tendencies subtly emerge, creating a permissive environment for early neurovascular injury and impaired cerebrovascular resilience. Methods: This narrative review integrates mechanistic evidence derived from experimental, clinical, and translational studies examining the interplay between oxidative stress, inflammatory signaling cascades, endothelial senescence, and blood–brain barrier (BBB) disruption across peripheral and cerebral microvascular systems. A comparative framework was applied to PAD and cerebral microcirculatory pathology to identify convergent molecular drivers and systemic mechanisms underlying endothelial deterioration. Results: Accumulating evidence demonstrates that oxidative stress disrupts endothelial mitochondrial function, compromises tight junction architecture, and accelerates angiogenic failure. Concurrent inflammatory activation amplifies these alterations through cytokine-mediated endothelial activation, enhanced leukocyte adhesion, and promotion of a pro-thrombotic microenvironment. Progressive endothelial senescence consolidates these insults into a persistent state of microvascular dysfunction characterized by diminished nitric oxide bioavailability, capillary rarefaction, and compromised barrier integrity. Notably, these pathological features are shared between PAD and the aging cerebral circulation, reinforcing the concept of a unified systemic microvascular aging phenotype. Conclusions: Microvascular failure in the aging brain should be understood as an extension of systemic endothelial deterioration driven by oxidative stress, chronic inflammation, and senescence-associated vascular exhaustion. Recognizing the shared molecular architecture linking peripheral and cerebral microcirculatory dysfunction offers a strategic framework for developing targeted therapeutic interventions aimed at restoring endothelial resilience, stabilizing BBB integrity, and preserving neurovascular homeostasis in aging populations. Full article

Background/Objectives: Impaired intestinal barrier function is a hallmark of inflammatory bowel disease (IBD). Akkermansia muciniphila and its outer membrane protein Amuc_1100 can enhance this barrier, but the clinical application of Amuc_1100 is limited by the fastidious growth of its native host. This study aimed to overcome this by utilizing the robust probiotic Lacticaseibacillus paracasei L9 for targeted Amuc_1100 delivery. Methods: We engineered Lc. paracasei L9 to express Amuc_1100 via intracellular (pA-L9), secretory (pUA-L9), and surface-display (pUPA-L9) strategies. Their efficacy was assessed in Lipopolysaccharide (LPS)-induced macrophages and a dextran sulfate sodium (DSS)-induced colitis mouse model, evaluating inflammation, barrier integrity, and mucosal repair. Results: The secretory (pUA-L9) and surface-display (pUPA-L9) strains most effectively suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in macrophages. In mice, both strains alleviated colitis and outperformed native A. muciniphila in improving disease activity. Crucially, they exhibited distinct, specialized functions: pUA-L9 acted as a systemic immunomodulator, reducing pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), elevating anti-inflammatory mediators (IL-4 and IL-10), and promoting goblet cell differentiation; notably, the inhibitory effect of pUA-L9 on IL-6 expression was approximately 2-fold greater than that of pUPA-L9. In contrast, pUPA-L9 excelled in local barrier repair, uniquely restoring mucus layer integrity (Muc1, Muc2, and Tff3) and reinforcing tight junctions (ZO-1, Occludin, Claudin1, Claudin3, and Claudin4). In particular, pUPA-L9 increased Muc2 expression by approximately 3.6-fold compared with pUA-L9. Conclusions: We demonstrate that the subcellular localization of Amuc_1100 within an engineered probiotic dictates its therapeutic mode of action. The complementary effects of secretory and surface-displayed Amuc_1100 offer a novel, spatially targeted strategy for precision microbiome therapy in IBD. Full article

Per- and Polyfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals increasingly associated with adverse health outcomes. The gastrointestinal tract represents both a major route of exposure and a key target of PFAS toxicity. This review integrates updated evidence on how PFAS compromise intestinal homeostasis through interrelated structural, metabolic, and immunological mechanisms. PFAS disrupt epithelial integrity by down-regulating tight-junction proteins, inducing oxidative stress, and activating inflammasome signaling. Concurrently, metabolic reprogramming and PFAS-driven microbial dysbiosis contribute to barrier dysfunction and altered production of signal/metabolic molecules. These alterations may link environmental exposure to chronic intestinal inflammation and increase susceptibility to inflammatory bowel disease and related metabolic disorders. By synthesizing recent findings, key mechanistic gaps were highlighted also emphasizing the need for integrative experimental and translational studies to refine risk assessment in humans and develop preventive and therapeutic strategies. Full article

Background: Enterococcus faecalis is an opportunistic pathogen that is capable of causing bacterial encephalitis under specific pathological conditions. MicroRNAs (miRNAs) are a class of small, single-stranded non-coding RNAs, typically approximately 21 nucleotides in length. As master regulators of gene expression, they orchestrate critical pathways across diverse organisms and a broad spectrum of diseases; however, their role during E. faecalis neuro-invasion remains unexplored. Methods: A lamb model of E. faecalis-induced encephalitis was established. Integrated analysis of high-throughput sequencing data identified oar-miR-29b as a key differentially expressed miRNA during infection. To first verify its association with inflammation, primary SBMECs were stimulated with lipoteichoic acid (LTA), confirming that oar-miR-29b expression was significantly upregulated under inflammatory conditions. Subsequently, independent gain- and loss-of-function experiments in SBMECs were performed, with inflammatory cytokine expression assessed by qPCR and tight-junction protein levels evaluated by Western blotting. Results: Functional studies demonstrated that oar-miR-29b acts as a pro-inflammatory mediator, significantly upregulating IL-1β, IL-6, and TNF-α while degrading tight-junction proteins (ZO-1, occludin, and claudin-5), thereby compromising endothelial barrier integrity. Mechanistically, bioinformatic prediction and dual-luciferase reporter assays confirmed C1QTNF6 as a direct target of oar-miR-29b. The oar-miR-29b/C1QTNF6 axis is thus defined as a novel regulatory pathway contributing to neuro-inflammation and blood-brain barrier disruption. Conclusions: Collectively, our findings identify the oar-miR-29b/C1QTNF6 axis as a novel pathogenic mechanism that exacerbates E. faecalis-induced neuroinflammation and blood-brain barrier disruption. Full article

Background/Objectives: Antibiotic-associated diarrhea (AAD) arises from antibiotic-induced disruption of microbial diversity, metabolic activity, epithelial integrity, and mucosal immunity. Probiotics are widely used but often show limited efficacy under antibiotic pressure. Herbal and natural products (HNPs) may provide multi-target benefits by modulating microbiota-dependent and host-directed pathways. This review synthesized animal studies evaluating HNP or HNP–probiotic combination (HNP–C) therapies using molecular microbiome endpoints. Methods: Following PRISMA 2020 guidelines, controlled in vivo studies assessing HNP or HNP–C interventions for AAD were searched in Pubmed, EMBASE, Web of Science, Scopus, and CNKI through November 2025. Eligible studies reported microbial diversity, taxonomic shifts, short-chain fatty acids (SCFAs), barrier markers, or immune responses. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, findings were narratively synthesized. Results: Twenty-seven studies met inclusion criteria (21 HNP, 6 HNP–C). HNP monotherapies consistently improved α-diversity, shifted β-diversity toward healthy controls, restored SCFA-producing taxa, and increased SCFA levels. They also enhanced tight junction proteins and reduced inflammatory cytokines. HNP–C interventions demonstrated more comprehensive microbial, epithelial, and immune recovery; however, only two studies included direct comparisons among HNP-only, probiotic-only, and combination groups. In these, HNP–C showed greater improvements than individual components, suggesting complementary or potentially complementary or additive effects. Other HNP–C studies were limited by absent comparator arms. Conclusions: HNPs appear to support recovery of microbial diversity, metabolic function, epithelial barrier integrity, and immune regulation by engaging microbiota-dependent and host-mediated mechanisms. HNP–C strategies may offer complementary benefits, although rigorously controlled comparative studies and clinical validation remain needed. Full article

Goose astrovirus 2 (GAstV-2) infection leads to visceral gout and swollen kidneys in goslings, causing a 5–50% mortality rate and significant economic losses for goose flocks. While most studies on the virus’s pathological damage have focused on the kidneys, few reports have examined the effects of this fecal-oral pathogen on the digestive system. This study investigated GAstV-2 localization, cellular targets, and its impact on intestinal structure and homeostasis in orally infected goslings. Twenty 1-day-old goslings were randomly assigned to the infected and control groups. Clinical signs, organ lesions, viral distribution, histopathology, and alterations in intestinal cell populations, cytokine expression, and signaling pathways were assessed at 7 days post-infection. GAstV-2 was detected in the duodenum, jejunum, ileum, cecum, and rectum, with the highest viral load in duodenal crypt cells. Infection induced crypt cell necrosis, reduced villus height, decreased villus-to-crypt ratio, and lowered numbers of goblet cells and Lgr5+ intestinal stem cells. In contrast, Paneth cell abundance, Bmi1+ stem cells, and tight junction-related gene expression increased. Inhibition of stem cell differentiation into goblet cells was observed, mediated by modulation of the Notch signaling pathway. Proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-22, and TNF-α, were markedly upregulated, indicating a strong inflammatory response. These results demonstrate that GAstV-2 preferentially targets duodenal crypt cells, disrupts epithelial renewal, and impairs mucosal barrier function, while triggering compensatory regenerative and immune mechanisms. This study provides new insights into the intestinal pathogenesis of GAstV-2 and identifies potential targets for interventions to mitigate intestinal injury and economic losses in gosling production. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event triggered by antiresorptive and/or anti-angiogenic agents, characterized by bone destruction, sequestrum formation, and refractory mucosal defects. Effective mucosal healing can be a critical factor for MRONJ prevention and treatment. While endoplasmic reticulum stress (ER stress) has been implicated in tissue repair, its role in MRONJ-associated mucosal healing impairment remains undefined. This study investigated the effects of the anti-angiogenic drug sunitinib on oral mucosal healing and its underlying mechanisms. A mouse model of palatal mucosal defects was established, RNA-seq, transmission electron microscopy, and morphological analyses were used to assess how sunitinib affects ER function during mucosal repair. Using human oral keratinocytes (HOKs), we further elucidated the subcellular mechanisms through which sunitinib influences cell proliferation, migration, cell cycle progression, tight junctions, and apoptosis via techniques such as qPCR, Western blotting, immunofluorescence, and flow cytometry. Our findings demonstrated that sunitinib might induce significant alterations in the morphology of the ER and mitochondria. Both in vivo and in vitro experiments revealed that sunitinib persistently activates the GRP78 (BIP)/PERK/ATF4/CHOP axis in HOKs. This sustained ER stress can inhibit keratinocytes migration and proliferation, disrupt tight junctions, and trigger the intrinsic mitochondrial apoptotic pathway, ultimately leading to impaired oral mucosal healing and barrier dysfunction. Critically, pharmacological inhibition of ER stress was shown to restore keratinocytes’ function and promote effective mucosal healing. These results indicated that targeting sunitinib-induced persistent ER stress might represent a promising therapeutic strategy to prevent and treat oral mucosal toxicity associated with this drug. Full article

The exopolysaccharides (EPS) from the mycelial fermentation of Cordyceps sinensis Cs-HK1, especially the low-molecular weight, protein-rich exopolysaccharide fractions (EPS-LM), have previously exhibited significant antioxidant activity. This study further investigated the antioxidant and protective effects of EPS-LM on intestinal epithelial barrier integrity in Caco-2 monolayers challenged with hydrogen peroxide (H₂O₂, 550 μM). EPS-LM contained two major molecular-weight fractions, 25 kDa and 1.7 kDa, with 19.3% total carbohydrate and 28.7% protein content (w/w). Treatment of the cells with EPS-LM (50–200 μg/mL) showed concentration-dependent protective effects against ROS-induced losses of cell viability and epithelial barrier integrity. EPS-LM treatment enhanced the activities of major antioxidant enzymes (SOD, GSH-Px, and CAT) and modulated NRF2 and its downstream target NQO1, consistent with alleviated oxidative stress. It also improved several indicators of intestinal barrier function, including increased transepithelial electrical resistance and upregulation of tight junction proteins (Occludin, ZO-1, and Claudin-1). These results provide new experimental evidence and theoretical basis for the nutraceutical potential of EPS-LM to mitigate oxidative stress and preserve intestinal epithelial barrier integrity. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) is a leading cause of death among forms of gynecologic cancer. Significant causes of mortality include high recurrence rates and the development of resistance to platinum-based chemotherapy. This highlights the need for reliable prognostic biomarkers to improve patient stratification and inform treatment decisions. Claudin-4, a tight junction protein frequently overexpressed in epithelial tumors, has been associated with tumor progression and resistance to chemotherapy. Methods: We retrospectively analyzed 83 patients with EOC who underwent debulking surgery. Claudin-4 expression was assessed by immunohistochemistry and categorized as high or low based on a semi-quantitative scoring system. Survival outcomes were evaluated using Kaplan–Meier analysis and Cox regression. Predictors of platinum resistance were examined using logistic regression. Results: High Claudin-4 expression was observed in 55.4% of cases and was associated with significantly shorter disease-free survival (DFS) (23 vs. 66 months, p = 0.00024) and overall survival (OS) (85 months vs. NR, p = 0.0031). In multivariable analysis, platinum resistance (DFS; HR 4.99, OS; HR 4.27) and high Claudin-4 expression (DFS; HR 2.46, OS; HR 3.59) were independent predictors of poor outcomes. Logistic regression further demonstrated that high Claudin-4 expression and interval debulking surgery were independent predictors of platinum resistance. Conclusions: High Claudin-4 expression was associated with inferior survival and an increased risk of platinum resistance in EOC. Our findings suggest that Claudin-4 may serve as a negative prognostic biomarker and a potential therapeutic target. Future prospective studies are warranted to further elucidate the underlying mechanisms and validate Claudin-4’s clinical utility. Full article

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated significant cardiovascular and renal benefits beyond glycemic control, yet their integrated mechanisms remain incompletely understood. Emerging evidence highlights the gut-kidney-heart axis as a pivotal pathological network, wherein gut dysbiosis, toxic metabolite accumulation, intestinal barrier disruption, and systemic inflammation synergistically drive cardiorenal injury. This review systematically elucidates how SGLT2i modulate this axis through multi-level interventions: reshaping gut microbiota composition, enriching short-chain fatty acid-producing bacteria, suppressing trimethylamine and other toxin-generating microbes, restoring tight junction integrity, and regulating bile acid metabolism. These upstream effects reduce systemic inflammatory and metabolic stress, interrupt kidney-derived toxin amplification, and mitigate myocardial remodeling. Unlike previous reviews focusing on single-organ pathways, this work integrates microecological regulation, metabolite reprogramming, and cross-organ protection into a unified “three-axis convergence to the heart” framework. We also highlight potential species-specific microbiota regulatory profiles among different SGLT2i and propose future directions, including fecal microbiota transplantation and microbiota-targeted co-therapies, to clarify causal relationships and optimize therapeutic strategies. By positioning the gut as a modifiable upstream driver, this framework provides novel mechanistic insight and translational potential for expanding SGLT2i applications in metabolic cardiovascular disease, including in non-diabetic populations. Full article

The restriction of antibiotics and therapeutic zinc oxide in piglet diets has increased challenges related to gut health and post-weaning performance. This study assessed the effects of a diet supplemented with organic acids and the probiotic Clostridium butyricum on intestinal integrity, fecal microbiota composition, and performance parameters in weaned piglets. Forty piglets were selected at weaning, and fecal samples were collected on day 0 and day 14 of supplementation. Gene expression of tight junction proteins (zonulin, occludin) and inflammatory markers (calprotectin, IFN-γ, TGF-β) was analyzed by PCR. Bacterial DNA quantification was used to evaluate microbiota changes. In addition, average daily gain (ADG), feed conversion ratio (FCR), and mortality were recorded across three feeding phases: CONTROL, TRANSITION, and 0M. No significant changes were found in tight junction protein expression post-weaning, but reductions in IFN-γ and TGF-β suggest improved immune modulation. Piglets in the TRANSITION and 0M groups showed higher ADG (CONTROL = 292.28 g/day; TRANSITION = 300.09 g/day; 0M = 307.45 g/day) and reduced mortality (CONTROL = 6.48%; TRANSITION = 5.10%; 0M = 5.08%) compared to CONTROL. These findings indicate that targeted dietary supplementation can support gut health and performance in weaned piglets, offering a promising alternative to medicated feed under current regulatory constraints. Further research is guaranteed to refine these strategies for broader application in sustainable pig production. Full article

Background: Pruritus is burdensome across dermatoses. Beyond Staphylococcus, broader components of the cutaneous microbiome—bacteria, fungi, and viruses—and their products shape itch via barrier disruption, immune polarization, and direct neurosensory activation. Methods: We conducted a narrative review of human and translational studies. PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to 27 August 2025 using terms for itch, skin microbiome, bacteriotherapy, proteases, PAR, TRP channels, IL-31, Malassezia, and AHR ligands. English and Italian records were screened; randomized trials, systematic reviews, and mechanistic studies were prioritized; and unsupported single case reports were excluded. Results: Beyond Staphylococcus aureus, microbial drivers include secreted proteases activating PAR-2/4; pore-forming peptides and toxins engaging MRGPRs and sensitizing TRPV1/TRPA1; and metabolites, especially tryptophan-derived AHR ligands, that recalibrate barrier and neuro-immune circuits. Commensal taxa can restore epidermal lipids, tight junctions, and antimicrobial peptides. Early studies of topical live biotherapeutics—Roseomonas mucosa and Staphylococcus hominis A9—report reductions in disease severity and itch. Fungal communities, particularly Malassezia, contribute via lipases and bioactive metabolites with context-dependent effects. Across studies, heterogeneous itch metrics, small samples, and short follow-up limit certainty. Conclusions: The cutaneous microbiome actively contributes to itch and is targetable. Future studies should prioritize standardized itch endpoints, responder stratification, and robust safety for live biotherapeutics. Full article