Search Results (8,835)

Background: Non-infectious uveitis (NIU) is an inflammatory ocular condition often associated with systemic immune-mediated disorders. The pathogenesis of NIU is complex and involves genes from the Human Leukocyte Antigen (HLA) class I system. Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves antigenic peptides to an optimal length for loading and presentation on HLA I molecules. In this systematic review, we aimed to summarize the current knowledge regarding how susceptibility to developing NIU is linked to single-nucleotide polymorphisms (SNPs) in the ERAP1 gene, a locus well known for its connection to autoinflammatory disorders. Methods: We performed a PRISMA protocol-guided systematic review in various databases. Results: Out of the 311 screened studies, only 12 met the inclusion criteria. Five of them are Genome-Wide Association Studies. We found relevant research for three types of NIU: acute anterior uveitis, Behçet’s uveitis, and birdshot chorioretinopathy. A frequently observed association between ERAP1 SNPs and disease risk was noted when analyzing the HLA-carriers (B*27, B*51, A*29), which points toward an epistatic interaction between ERAP1 and the MHC class I complex. Conclusions: Our findings suggest that ERAP1 gene variation is understudied in relation to NIU. A significant amount of research has also concentrated on risk stratification, and reliable markers for patient selection are needed, especially in view of emerging anti-ERAP therapies. Full article

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. Given the significant adverse effects and inconsistent long-term efficacy of conventional immunosuppressive strategies, there is an unmet need for safer adjunctive therapies. Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed as potential candidates to address this therapeutic gap. Purpose: This narrative review summarizes the proposed mechanisms of action of omega-3 PUFAs in IgAN and critically evaluates the current clinical evidence regarding their therapeutic potential and limitations. Mechanisms: Emerging experimental data suggest that omega-3 PUFAs may modulate inflammatory and fibrotic pathways relevant to kidney injury. Proposed mechanisms include modulation of eicosanoid metabolism, attenuation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, and generation of specialized pro-resolving mediators. In experimental studies, omega-3 PUFAs may also suppress nuclear factor kappa B (NF-κB)-driven transcription and attenuate mesangial cell proliferation, IgA immune-complex deposition, and transforming growth factor beta 1 (TGF-β1)/Smad3-mediated fibrotic signaling. Clinical Evidence: Conclusions: Omega-3 PUFAs have biological plausibility as adjunctive therapy in IgAN, but their clinical benefit remains uncertain. Available randomized trials and meta-analyses suggest possible modest effects on proteinuria in some settings, whereas evidence for preservation of kidney function or prevention of kidney failure is inconsistent and of low certainty. Future well-designed trials incorporating guideline-directed background therapy and biomarker-guided patient selection are essential to determine optimal dosing, formulation, biological exposure, and whether any patient subgroups derive clinically meaningful benefit. Full article

Periodontitis (PD), the second most prevalent oral disease, contributes to systemic health issues and results from a complex interaction between microbial dysbiosis and host immune responses, strongly shaped by genetic background. This pilot case–control study evaluated associations between five inflammation-related variants (IL1A rs1800587, IL1B rs1143634, IL1B rs16944, IL1RN rs4251961, TNFA rs1800629) and PD susceptibility in Portuguese postpartum women. Eighty-eight women (33 PD patients and 55 controls) were genotyped using iPLEX Gold technology. Associations were tested using logistic regression models, with multiple-testing correction applied to adjust significance thresholds. TNFA rs1800629 was associated with PD in the collapsed model (GA+AA vs. GG; OR = 3.3, p < 0.05). IL1RN rs4251961 showed strong associations across all models. In the codominant model, heterozygotes had increased PD odds (OR = 3.52, adjusted p < 0.05), while CC homozygotes showed 8-fold odds (OR = 8.1, adjusted p < 0.05). The collapsed model was also significant (p < 0.05). The remaining variants were not associated with PD. IL1RN rs4251961 may represent a novel genetic marker for PD, with clinical relevance given its inflammatory role and therapeutic use of recombinant IL-1RA in chronic inflammatory diseases. This first report linking IL1RN rs4251961 to PD supports validation in larger European cohorts. Full article

Depression is a prevalent and complex neuropsychiatric disorder that substantially impairs quality of life worldwide. Current pharmacological and psychotherapeutic interventions are often limited by inadequate efficacy and restricted accessibility. Exercise has emerged as a potent non-pharmacological alternative, exhibiting antidepressant effects comparable to conventional treatments, with the microbiota–gut–brain (MGB) axis increasingly recognized as a key mediator. Despite growing interest, existing research articles largely describe associations without mapping the molecular pathways from exercise-altered microbes to neurobiological changes in depression. This review addresses these gaps by comprehensively dissecting the molecular cascades from microbial remodeling to synaptic and systemic adaptations, thereby providing a mechanistic roadmap absent in current syntheses. We first delineate how gut dysbiosis contributes to depression via endocrine, neural, and immune pathways. Subsequently, we highlight the ability of exercise to reverse these pathological states by restoring microbial diversity, reinforcing intestinal barrier function, and modulating the production of microbial metabolites. These exercise-driven changes collectively attenuate systemic and neuroinflammation, enhance brain-derived neurotrophic factor signaling, augment serotonin synthesis, and dampen hypothalamic–pituitary–adrenal axis hyperactivity. By reinstating intestinal homeostasis, exercise acts as a central regulator of the MGB axis and represents a promising therapeutic strategy. This integrative framework offers novel insights into depression pathogenesis and opens avenues for multifaceted intervention. Full article

This study evaluated the effects of dietary supplementation with a commercial lactoferrin–osteopontin complexes preparation (LF-OPN; LF:OPN mass ratio 8:1; 240 mg/kg body weight) on growth, immune indices, antioxidant status, intestinal barrier-related markers, fecal microbiota, short-chain fatty acids (SCFAs), peripheral lymphocyte subsets, and the whole-blood transcriptome of growing British Shorthair kittens. Sixteen kittens were randomly assigned to either a basal diet group (CON) or a group supplemented with LF-OPN complexes (LFT) for 28 days. LF-OPN supplementation did not significantly affect body weight or average daily gain. On D28, the LFT group had a higher serum immunoglobulin M concentration and a lower tumor necrosis factor-α concentration (p < 0.05). Serum superoxide dismutase and glutathione peroxidase activities and total antioxidant capacity were higher, whereas malondialdehyde was lower (p < 0.05) in the LFT group (p < 0.01). Fecal 16S rRNA gene sequencing revealed no significant difference in alpha diversity; howerer, LEfSe identified selective taxonomic difference, including higher relative abundances of Holdemanella and Erysipelotrichaceae and lower relative abundances of Enterobacteriaceae and Escherichia-Shigella in the LFT group. Fecal short-chain fatty acid concentrations were unchanged. Flow cytometry revealed a higher proportions of peripheral CD4+ lymphocytes and a higher CD4+/CD8+ ratio in the LFT group (p < 0.01), whereas the CD8+ proportion was unchanged. Whole-blood RNA sequencing identified 283 differentially expressed genes (199 upregulated and 84 downregulated), with enrichment of immune-related pathways including hematopoietic cell lineage, antigen processing and presentation, cytokine–cytokine receptor interaction, NF-κB signaling, and IL-17 signaling, but these findings were not independently validated. The tested LF-OPN preparation was well tolerated and was associated with elevated antioxidant status, altered immune indices, and selective modulation of the fecal microbiota in growing kittens. The study does not establish synergy or identify the individual contributions of either protein. Full article

Klebsiella pneumoniae infection following H9N2 Influenza A virus (IAV) infection causes severe pneumonia. But the underlying pathogenic mechanisms of H9N2 IAV and K. pneumoniae co-infection are complex and need to be further explored. In this study, the lung transcriptomes of mice with H9N2 IAV and K. pneumoniae co-infection were characterized by transcriptomic profiling. As a result, GO enrichment analysis revealed that the differential genes were primarily involved in the activation of immune responses, cellular components of membranes and extracellular spaces, and defense responses against pathogen infections. According to KEGG enrichment, the differentially expressed genes (DEGs) were concentrated in TLR signaling pathways, RLR signaling pathways, TNF signaling pathways and NLRP3 signaling pathways. Furthermore, in vitro cell models were established to investigate the innate immune responses induced by H9N2 IAV and K. pneumoniae CPS co-stimulation. K. pneumoniae CPS stimulation influenced the cytokine profiles of mink lung epithelial cells infected with H9N2 IAV, worsened cell viability, and aggravated apoptosis, indirectly inhibiting H9N2 IAV replication. The findings demonstrated that K. pneumoniae superinfection modulated the innate immune responses induced by H9N2 IAV infection, contributing to its pathogenesis. Full article

In modern societies, the renewed concept of food as medicine coexists with unprecedented consumption of highly processed foods, food additives, environmental xenobiotics, and pharmacological agents, contributing to the increasing prevalence of metabolic and degenerative diseases and accelerated aging. Although modern pharmacotherapies have transformed disease management, long-term drug exposure introduces additional metabolic burdens, off-target effects, and cumulative toxicities that are profoundly influenced by nutritional status. Collectively, dietary constituents, environmental chemicals, endogenous metabolic by-products, and therapeutic agents constitute a complex exposome that requires continuous recognition, utilization, detoxification, and clearance. Within this context, the liver sinusoidal clearance system (LSCS) emerges as a central regulator of systemic homeostasis. We propose a conceptual framework in which circulating molecules are classified as self (S), modified self (M), and foreign (F) molecules according to their physiological handling by the LSCS. Through coordinated hepatic utilization of S molecules and selective clearance of M and F molecules, fenestrated liver sinusoidal endothelial cells (LSECs) maintain metabolic homeostasis, immune tolerance, and physiological pharmacokinetics. Conversely, chronic dietary overload, poor dietary quality, food processing, and sustained exposure to pro-inflammatory and oxidative dietary and environmental molecules initiate chronic low-grade inflammation, which promotes LSEC capillarization, impairs hepatic clearance, increases the modification of S molecules into M molecules and establishes a feed-forward cycle that further amplifies chronic inflammation and metabolic dysfunction. Finally, we discuss recent advances in the programmable modulation of the LSCS, including its transient suppression to prolong therapeutic exposure and its activation to enhance the clearance of metabolically harmful M and F molecules through coordinated upregulation of the endoglin–stabilin-2–FcγRIIb axis and the LSEC markers Oit3 and Dnase1L3. We highlight dual-function supramolecular nanofiber platforms that enable bidirectional regulation of the LSCS through nanofiber complexes with therapeutic proteins, thereby expanding their therapeutic potential and enhancing efficacy in the treatment of metabolic, inflammatory, and age-related diseases. Full article

Major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells (IECs) has emerged as a critical mechanism regulating mucosal immune homeostasis at the interface between the intestinal microbiota, epithelial barrier, and immune system. Beyond professional antigen-presenting cells, IEC-intrinsic MHC-II shapes CD4⁺ T-cell responses, influencing tolerance to commensal microorganisms, immunity to enteric pathogens, and maintenance of barrier integrity. Recent studies have revealed that epithelial MHC-II expression is dynamically regulated by cytokines, the gut microbiota, dietary factors, and microbiota-derived metabolites, linking environmental signals to local adaptive immune responses. Dysregulation of epithelial antigen presentation has been implicated in chronic intestinal inflammation, including inflammatory bowel disease (IBD). This review summarizes current knowledge regarding the molecular regulation, spatial organization, and immunological functions of epithelial MHC-II and discusses its emerging role in host–microbiota interactions, mucosal barrier homeostasis, and intestinal disease. Full article

Lung cancer is characterized by profound molecular and clinical heterogeneity and remains the leading cause of cancer-related mortality worldwide. Its initiation and progression are shaped by complex genetic and epigenetic alterations that perturb key biological processes, including cell proliferation, apoptosis, metabolic reprogramming, invasion, metastasis, and immune evasion. Increasing evidence indicates that dysregulated alternative splicing (AS) represents a critical post-transcriptional regulatory mechanism involved in lung cancer pathogenesis. Although AS abnormalities are not the sole drivers of tumorigenesis, they contribute to malignant transformation, tumor progression, therapeutic resistance, and phenotypic plasticity, providing opportunities for biomarker development and therapeutic targeting. This review summarizes the multifaceted roles of AS in lung cancer biology, highlighting its contributions to tumor evolution, metastatic dissemination, and treatment resistance. Furthermore, subtype-specific AS landscapes between major lung cancer subtypes are discussed to elucidate their distinct molecular mechanisms and therapeutic implications. Representative AS-generated isoforms, including cluster of differentiation 44 variants (CD44v), are further discussed as examples of how aberrant splicing events regulate cancer stemness, tumor progression, and therapeutic responses. The regulatory mechanisms underlying CD44v generation, including upstream splicing factors and downstream signaling pathways, are also summarized. Collectively, this review highlights the emerging role of aberrant AS regulation in lung cancer and emphasizes its potential implications for biomarker discovery and precision therapeutic strategies targeting splicing dysregulation. Full article

Alzheimer’s disease (AD) has a complex pathogenesis, involving molecular and neuroimmune dysregulation, but the causal drivers linking transcriptomic changes to immune remodeling are not yet clear. In a discovery cohort, differential expression analysis was performed, and it was independently validated in two external cohorts. Key genes were prioritized via LASSO/logistic regression, functionally annotated, and causally linked to AD using two-sample MR. The neuroimmune landscape was mapped by ssGSEA, and top candidates were validated in vitro. RGS1 is a key node in neuroinflammation and cytoskeletal dynamics, which is prioritized by the algorithmic intersection. MR analysis suggested a potential causal association between genetically predicted RGS1 expression and AD risk. RGS1 was consistently upregulated in both discovery and validation cohorts (AUC: 0.61–0.67) and was confirmed in vitro. Immune deconvolution showed that AD-specific enrichment profiles occur, and RGS1 is strongly correlated with activated CD4+ T cells and pro-inflammatory chemokines. RGS1 is identified as a robust key gene that may contribute to immune microenvironment dysregulation in AD, and combining discovery-validation transcriptomics, causal inference, and experimental validation, we find that RGS1 is a potential immunomodulatory target. Full article

By damaging target tissues and compromising the host immune system, Myxobolus cerebralis and Tetracapsuloides bryosalmonae remain persistent threats to salmonids. RNA sequencing was used to assess transcriptome modulation in the kidney and head cartilage (HC) of rainbow trout during single and co-infections with these two myxozoan parasites. Fish were exposed to M. cerebralis (Mc) and T. bryosalmonae (Tb), and 30 days later, half of the fish from each group were subjected to sequential co-infections (Mc⁺ and Tb⁺). This assessment aimed to evaluate the combined effects of both pathogens. Transcriptomic analysis was conducted using kidney and HC tissues collected 60 days post-co-infection. The results showed that infection order altered host transcriptional profiles in a tissue-dependent manner. In the kidney, Tb fish showed pronounced transcriptional alterations linked to chronic inflammation, immune complex clearance, and IL-8-mediated responses. Tb⁺ fish exhibited broad immune activation in the kidney, suggesting dysregulated inflammatory responses likely associated with subsequent infection with M. cerebralis. In the kidney of Mc⁺ fish, the immune response was characterized by macrophage and IL signaling pathways. In HC, Mc fish activated Th17, IL-23, phagolysosome, and IL-6 cytokine pathways. In contrast, Mc⁺ fish showed increased pathogen processing and enhanced metabolic responses accompanied by suppression of cytokines and tissue repair processes. HC responses in Tb⁺ fish shifted toward IL-23, Th17-driven responses, alongside reduced developmental and extracellular matrix processes. The study establishes that host responses to myxozoan co-infection are shaped by tissue tropism and infection sequence, with distinct immune and tissue remodeling pathways activated in the target organs. These findings enhance the understanding of sequential T. bryosalmonae and M. cerebralis infections and provide a basis for identifying tissue-specific biomarkers and key immune targets. The findings may help identify methods for improved monitoring and management of myxozoan infections in salmonids. Full article

Cranial bone defects remain a significant clinical challenge due to their limited intrinsic regenerative capacity and the complexity of coordinating osteogenesis, angiogenesis, and immune responses within a confined and poorly vascularised environment. Conventional approaches, including autologous grafts and synthetic implants, provide structural support but fail to actively modulate the biological processes required for effective bone regeneration. In this context, hydrogel-based systems have emerged as versatile platforms for localized and controlled drug delivery in cranial bone tissue engineering (BTE). This review provides a comprehensive overview of hydrogel-based delivery strategies designed to regulate the spatiotemporal presentation of bioactive agents within cranial defects. The main classes of hydrogels, natural, synthetic, semi-synthetic, and hybrid systems, are discussed in relation to their physicochemical properties and suitability for drug delivery applications. Current delivery approaches are analysed, including cell-free systems (growth factors, peptides, bioactive ions, nucleic acids, and small molecules drugs), cell-based platforms, and multifunctional systems integrating secondary carriers such as nanoparticles (NPs), microparticles (MPs), and extracellular vesicles (EVs). Particular emphasis is placed on how hydrogel design parameters, including crosslinking density, degradation kinetics, and responsiveness to microenvironmental cues, govern therapeutic release and influence regenerative outcomes. Emerging strategies and key translational challenges are also highlighted. Full article

The long interspersed element-1 (LINE-1) family is the sole remaining transposable element family that is capable of autonomous retrotransposition in humans. LINE-1 expression, tightly controlled through epigenetic mechanisms, has complex effects on gene regulation. Due to their similarity to retroviruses, once activated, LINE-1s have the ability to trigger pathways involved in innate and adaptive immunity with both beneficial and detrimental effects. This review will explore the mechanisms and importance of LINE-1 epigenetic repression and the potential outcomes of LINE-1 expression, with a focus on their immunogenic roles in innate and adaptive immunity. Full article

Background and aim: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from a complex interplay among genetic susceptibility, immune dysregulation, environmental factors, and alterations in the gut microbiota. Among these, diet has emerged as a key modifiable factor influencing intestinal inflammation, barrier integrity, and disease progression. This review aims to critically evaluate the role of dietary patterns and food additives in the pathogenesis and management of Crohn’s disease, with particular emphasis on their effects on intestinal inflammation, epithelial barrier function, and host–microbiota interactions. Methods: A comprehensive literature search was conducted using the PubMed, Scopus, and Web of Science databases up to March 2026. Clinical trials, observational studies, and mechanistic research were included based on their relevance to dietary factors, food additives, and intestinal inflammation in CD. Evidence was synthesized narratively to integrate clinical and experimental findings. Results: Dietary interventions such as the Crohn’s disease exclusion diet (CDED), specific carbohydrate diet (SCD), low-FODMAP diet, and Mediterranean diet (MD) demonstrate varying degrees of efficacy in improving clinical symptoms and, in some cases, inflammatory markers. In contrast, high consumption of ultra-processed foods is consistently associated with increased disease risk and activity. Emerging evidence highlights the role of food additives—particularly emulsifiers and artificial sweeteners—in disrupting gut barrier integrity, promoting dysbiosis, and enhancing inflammatory responses. Recent human studies further suggest that exposure to these compounds may correlate with disease activity, supporting their potential role in CD pathophysiology. Conclusions: Diet plays a significant adjunctive role in the management of Crohn’s disease. Reducing exposure to ultra-processed foods and potentially harmful food additives, while promoting balanced dietary patterns, may improve clinical outcomes. Further research is needed to clarify long-term effects and to develop personalized, evidence-based nutritional strategies for patients with CD. Full article

Background/Objectives: Breast implants are widely used in aesthetic and reconstructive surgery. Although they are not associated with an increased risk of breast carcinoma, growing attention has focused on implant-associated conditions, including breast implant-associated malignancies, breast implant illness (BII), and autoimmune or inflammatory manifestations. This review examines current evidence and explores the potential role of chronic inflammation and the host–implant–microbiome interface in these conditions. Methods: A narrative review was conducted focusing on implant-associated malignancies, BII, autoimmune manifestations, chronic inflammation, implant-associated biofilms, and host–implant interactions. Evidence from oncology, immunology, microbiology, and biomaterials research was integrated to evaluate potential mechanisms underlying implant-associated local and systemic manifestations. Results: Recent evidence suggests that prolonged host–implant interactions, persistent foreign body responses, implant-associated biofilms, microbial persistence, and chronic immune stimulation may contribute to long-term alterations within the peri-implant environment. These mechanisms have been proposed as potential contributors to breast implant-associated malignancies, as well as to systemic manifestations such as BII and autoimmune or inflammatory conditions. Although BII and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) have received increasing attention, causal relationships with breast implants remain unproven, and available evidence is limited by methodological heterogeneity, lack of standardized diagnostic criteria, and potential confounding factors. Conclusions: Emerging evidence highlights a complex interplay among implanted biomaterials, microbial biofilms, and host immune responses. The host–implant–microbiome interface may promote a biological environment that promotes persistent immune stimulation and chronic low-grade inflammation, providing a biologically plausible framework for interpreting heterogeneous implant-associated conditions. Further studies are needed to clarify the role of host–implant–microbiome interactions in implant-associated local and systemic manifestations. Full article