Search Results (10,455)

Background/Objectives: Ustekinumab, targeting the shared p40 subunit of interleukin (IL)-12 and IL-23, is an effective therapy for Crohn’s disease (CD), yet reliable predictors of response remain lacking. Given the central role of the IL-12/IL-23 axis in intestinal inflammation, we aimed to characterize the baseline mucosal expression of IL-12/IL-23 pathway components in lamina propria immune cells, and to explore their association with clinical response and remission following ustekinumab therapy. Methods: In this prospective, single-center study, biopsy-derived lamina propria mononuclear cells (LPMCs) were obtained from patients with CD prior to ustekinumab initiation. Gene expression of IL-12/IL-23 cytokine subunits and receptors was assessed by quantitative real-time PCR. Flow cytometry was performed to evaluate the distribution of T helper and innate lymphoid cell subsets and the expression of IL-23R and IL-12Rβ2. Clinical outcomes were assessed at week 16. Results: Fifteen consecutive patients were enrolled and included in the study. At week 16, 14/15 (93.3%) and 9/15 (60.0%) of patients reached clinical response and remission, respectively. No statistically significant differences in baseline mucosal gene expression of IL-12/IL-23 pathway components were observed between remitters and non-remitters. A trend toward higher expression of receptor subunits (IL23R, IL12RB1, IL12RB2) was observed in remitters, albeit with high variability and overlapping distributions. Similarly, cytokine subunits (IL23p19, IL12/IL23p40, IL12p35) showed no consistent differential expression pattern between the groups. In contrast, flow cytometry revealed a significantly higher frequency of IL-23R-expressing Th1 cells in remitters compared with non-remitters (20.6% vs. 6.8%, p = 0.009). Conclusions: Baseline transcriptional profiling of IL-12/IL-23 pathway components was not associated with remission following ustekinumab therapy. However, increased expression of IL-23R on mucosal Th1 cells identified a distinct immunological signature associated with clinical remission, suggesting that IL-23R expression on mucosal Th1 cells may represent a promising candidate biomarker that requires validation in larger independent cohorts. Full article

Background: Chronic rhinosinusitis with nasal polyps, CRSwNP, represents one of the most clinically relevant models of type 2 inflammation in the upper airways. Its pathogenesis is not sustained by a single mechanism but by the continuous interaction between epithelial barrier damage, immune activation and tissue remodeling. Although several systemic biomarkers are currently used in clinical practice, they do not always reflect the inflammatory processes occurring directly within the sinonasal mucosa. Objective: This review discusses nasal cytology as a local and clinically accessible read-out of type 2 inflammation and epithelial barrier dysfunction in CRSwNP. Particular attention is given to the relationship between cytological patterns, underlying immune mechanisms and the use of biologic therapies. Methods: A narrative review of the literature was conducted, focusing on epithelial barrier abnormalities, type 2 inflammatory pathways, cytological phenotypes and available monoclonal antibodies. The clinical relevance of these elements was considered, with particular regard to patient stratification and therapeutic decision-making. Results: Epithelial barrier disruption promotes the release of alarmins such as TSLP, IL-25 and IL-33. These mediators activate both innate and adaptive type 2 immune responses and contribute to the persistence of mucosal inflammation. Nasal cytology allows direct assessment of the local inflammatory infiltrate and makes it possible to identify eosinophilic, mast cell-predominant and mixed eosinophil–mast cell patterns. These profiles appear to mirror different inflammatory settings. In particular, the coexistence of eosinophils and mast cells may identify patients with more severe, persistent or recurrent disease. When integrated into clinical tools such as clinical–cytological grading (CCG), nasal cytology may improve disease stratification, support follow-up and help orient biologic therapy according to the level of the inflammatory cascade predominantly involved. These cytological profiles may also support biologic treatment selection, therapeutic monitoring, and future tapering strategies by reflecting the predominant inflammatory pathway active at the mucosal level. Conclusions: Nasal cytology is a direct, reproducible and clinically useful approach for evaluating local inflammation in CRSwNP. By providing information from the mucosal site of disease, it complements systemic biomarkers and may support personalized therapeutic strategies and biologic treatment selection in CRSwNP. Full article

Nitric oxide (NO) is a small, highly reactive gaseous signaling molecule that plays diverse and context-dependent roles in microbial physiology and host–microbe interactions. Over the past decade, increasing evidence has revealed the dual nature of NO as both an antimicrobial effector and a signaling mediator involved in microbial stress responses, metabolism, biofilm dynamics, quorum sensing, virulence regulation, and symbiotic interactions. In microbial systems, NO influences adaptation to environmental stress and contributes to mechanisms associated with persistence and antimicrobial resistance. In host organisms, NO functions as a key component of innate immunity while also participating in beneficial interactions involving rhizobia, mycorrhizal fungi, and probiotic microorganisms. Despite its biological significance, accurate detection and quantification of NO remain challenging because of its transient nature, high reactivity, low physiological concentrations, and interference from related reactive oxygen and nitrogen species. Recent advances in biosensing technologies have substantially improved NO detection capabilities through the development of electrochemical, optical, enzyme-based, microfluidic, wearable, and implantable sensing platforms. These innovations are complemented by analytical techniques including electron paramagnetic resonance spectroscopy, mass spectrometry, fluorescence-based imaging, and advanced microscopy, which enhance sensitivity, specificity, and spatiotemporal resolution in complex biological environments. Concurrently, statistical and computational approaches—including sensor calibration models, multivariate analyses, machine learning algorithms, and bioinformatics pipelines—have become increasingly important for extracting biologically meaningful information from NO-related datasets. Unlike previous reviews that primarily focus on either NO biology or sensing technologies, this review integrates current knowledge of NO-mediated microbial physiology and host–microbe interactions with recent developments in biosensor engineering, analytical methodologies, statistical frameworks, and emerging artificial intelligence (AI)-driven data interpretation. We further highlight applications of NO detection in infectious disease diagnostics, antimicrobial screening, probiotic and biofertilizer evaluation, environmental microbiome monitoring, and real-time studies of symbiosis and infection. Finally, future directions including miniaturized sensing platforms, multi-omics integration, AI-assisted analytics, and sensor standardization are discussed. By unifying molecular, analytical, and computational perspectives, this review provides a multidisciplinary framework and roadmap for advancing NO-based research and translational applications across microbial, environmental, and host-associated systems. Full article

Chemotherapy resistance in triple-negative breast cancer (TNBC) remains a critical clinical challenge, with a substantial proportion of patients failing to achieve pathological complete response following neoadjuvant chemotherapy (NAC). Using an integrative single-cell RNA sequencing (scRNA-seq), bulk transcriptomic, and spatial proteomic framework, we aimed to identify the malignant epithelial subset driving this resistance and the intercellular signaling axes through which it reprograms the tumor microenvironment (TME). scRNA-seq analysis of NAC-treated breast tumors revealed a Fatty Acid–EMT co-expressing epithelial subset (FA-EMT) that is selectively enriched in the chemotherapy-resistant residuum. Critically, FA-EMT co-expression—rather than either program individually—most powerfully predicted chemotherapy resistance and reduced overall survival across two independent bulk transcriptomic cohorts comprising 277 TNBC patients (p < 0.001). CellChat ligand–receptor analysis established FA-EMT cells as the dominant TME signaling hub, deploying MDK–NCL and MIF–CD74–CXCR4 axes to simultaneously suppress adaptive and innate anti-tumor immunity via T-cell exhaustion, Treg activation, and the expansion of myeloid-derived suppressor cells. Spatial CyCIF validation in a published paclitaxel-resistant TNBC mouse model (n = 69 cores) confirmed significant Metabolic-EMT enrichment in resistant tumor cores (p = 0.0085) with physical co-localization with immunosuppressive MDSC and Treg populations. These findings establish the FA-EMT subset as a key cellular driver of treatment failure in TNBC and nominate MDK–NCL and MIF–CD74–CXCR4 as mechanistically grounded therapeutic targets with the potential to dismantle the FA-EMT-driven immunosuppressive niche and sensitize chemotherapy-resistant TNBC to cytotoxic treatment. Full article

Macrophage extracellular traps (METs) are chromatin-based structures released by activated macrophages and are increasingly recognized as distinct, context-dependent effectors of innate immunity. Although initially described in antimicrobial defense, METs are now implicated in sterile inflammation, autoimmunity, fibrosis, metabolic and vascular injury, organ-specific damage, and cancer. This review integrates dispersed evidence on MET biology across physiological and pathological settings, moving beyond neutrophil-centered interpretations of extracellular trap biology. We summarize the molecular composition, structural heterogeneity, major forms of METosis, and key regulatory pathways, including PAD-dependent chromatin remodeling, reactive oxygen species and calcium signaling, mitochondrial DNA release, extracellular DNA sensing, protease-mediated injury, and macrophage–stromal crosstalk. We also discuss the dual nature of METs as protective structures that can contain pathogens and amplify early innate responses, but also as pathogenic platforms when excessive, persistent, or insufficiently cleared. Overall, current evidence supports METs as functionally versatile macrophage-derived immune structures whose biological effects depend on the stimulus, tissue microenvironment, and disease context. By providing a unified framework, this review highlights the relevance of METs as potential biomarkers and therapeutic targets in inflammatory, fibrotic, vascular, autoimmune, and malignant diseases. Full article

Opioids are frequently prescribed for cancer pain management, yet accumulating evidence suggests that opioid exposure may be associated with inferior outcomes in patients also undergoing treatment with immune checkpoint inhibitors (ICIs). To synthesize mechanistic and clinical evidence linking opioids to the PD-1/PD-L1 axis, the literature was searched up to 18 January 2026, with study selection and data extraction focused on (i) cancer-cell and immune-cell effects of opioid agonism or antagonism on PD-1/PD-L1 biology, and (ii) clinical studies reporting ICI outcomes (progression-free survival, overall survival, or treatment duration) with concomitant opioid exposure. Preclinical studies support multiple, non-mutually exclusive mechanisms: opioids can induce PD-L1 in tumour cells, modulate innate-inflammatory pathways (including TLR4-linked cascades), promote dysfunctional T-cell phenotypes that reduce responsiveness to PD-1 blockade, and show context- and opioid-dependent effects. Clinical cohorts and meta-analytic datasets in non-small cell lung cancer and other tumour types report associations between opioid exposure (including higher morphine-equivalent dosing) and worse ICI outcomes. The intersection of opioid signaling with PD-1/PD-L1 biology likely operates across cancer cell-intrinsic and immune cell-intrinsic pathways, providing a mechanistic rationale for prospective evaluation of opioid-sparing strategies and/or peripheral opioid antagonism as adjuncts to checkpoint blockade. Full article

Anesthetic agents are widely used in aquaculture to facilitate handling, transport, surgery, vaccination, tagging, and other husbandry procedures. However, most previous reviews have primarily focused on induction time, recovery duration, and welfare outcomes, with comparatively limited emphasis on blood physiology as an indicator of systemic anesthetic safety. The present review synthesizes current evidence regarding hematological, hemato-biochemical, blood gas, and immunohematological alterations induced by major anesthetic classes in aquaculture species. Literature published between 2000 and 2026 was retrieved from Scopus, Web of Science, Google Scholar, PubMed, ScienceDirect, and Springer Nature databases, with approximately 150 studies included following structured screening. Available evidence indicates that anesthetic exposure frequently alters erythrocyte and leukocyte profiles, cortisol secretion, glucose and lactate metabolism, hepatic enzyme activity, electrolyte balance, acid–base regulation, and blood oxygen transport. Respiratory depression, hypercapnia, hypoxemia, and transient metabolic acidosis were recurrent consequences of deep anesthesia, particularly during prolonged exposure or unfavorable environmental conditions. Several anesthetics also modulated innate immune responses through alterations in complement activity, respiratory burst function, cytokine signaling, and leukocyte redistribution. Collectively, the review highlights blood physiology as an essential framework for evaluating anesthetic safety and improving welfare-oriented aquaculture practices. Full article

Hepatitis C virus (HCV) infection remains a major cause of chronic liver disease worldwide, with potential progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and extrahepatic disease. According to World Health Organization estimates, approximately 50 million people worldwide live with chronic HCV infection, and nearly 1 million new infections occur each year. In 2022, approximately 242,000 deaths were attributed to hepatitis C, mainly from cirrhosis and hepatocellular carcinoma. Chronic infection develops when antiviral immune response fails to eliminate the virus. Viral clearance requires early innate immune activation, effective antigen presentation, broad HCV-specific CD4⁺ and CD8⁺ T-cell responses and durable immune memory. Dendritic cells play a pivotal role in this process by linking innate and adaptive immunity. In chronic HCV infection, dendritic cells may be reduced in number and show impaired maturation, lower interleukin (IL)-12 production, higher IL-10 expression and weaker stimulation of HCV-specific CD4⁺ T-cell responses. This review discusses the role of dendritic cells (DCs) in HCV infection, with emphasis on DCs’ phenotype and function in acute and chronic disease. It also summarizes immune changes after direct-acting antiviral (DAA)-induced sustained virologic response (SVR), including partial recovery of innate immune responses and persistent residual immune dysregulation. When accessible and appropriately selected, modern direct-acting antiviral therapy substantially improves outcomes for patients with HCV infection. Full article

The MUCIN 1 (MUC1) gene evolved in eutherian mammals in association with the marked expansion of endogenous retroviruses (ERVs). MUC1 encodes the MUC1-C/M1C protein that protects barrier epithelia from exogenous viruses. Activation of M1C in response to loss of homeostasis induces STAT1 and the type I interferon (IFN-I) pathway. Studies in cancer cells have found that M1C regulates human ERV (HERV) expression by a STAT1-mediated mechanism. These discoveries have uncovered new insights into M1C-induced regulation of HERVs and other retrotransposons, such as LINE-1 (L1) and Alu. M1C signaling integrates retrotransposon transcription with induction of the counteracting apolipoprotein B mRNA-editing catalytic 3 (APOBEC3) genes that, like MUC1, first appeared in placental mammals. Activation of retrotransposons induces viral mimicry characterized as an IFN-I response that promotes innate anti-tumor immunity. Conversely, M1C protects cancer cells by sustained induction of the IFN-I pathway and immune evasion. This review posits that M1C-dependent regulation of retrotransposon and APOBEC3 expression represents an adaptive response exploited by cancer cells that promotes malignant progression. Full article

Inflammation is a critical protective response that maintains tissue homeostasis. However, persistent or dysregulated inflammation contributes significantly to the progression of cancer and neurodegenerative diseases. Recent advances in RNA biology have identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as key modulators of inflammatory signaling networks. These RNA molecules regulate key pathways such as NF-κB, STAT3, MAPK, and PI3K/AKT, thereby influencing immune responses, tumor progression, neuronal survival, and cellular stress adaptation. In parallel, RNA-sensing receptors, including Toll-like receptors and RIG-I-like receptors, connect innate immune activation with chronic inflammatory pathology. Emerging evidence further demonstrates that inflammatory RNAs participate in epigenetic regulation, intercellular communication, and inter-organ crosstalk through extracellular vesicles and exosomes. In cancer, RNA-mediated feedback loops sustain tumor-promoting inflammation, metastasis, and immune evasion, whereas in neurodegenerative disorders, they contribute to glial activation, neuronal dysfunction, and progressive neuroinflammation. This review examines the mechanistic relationship between RNA dysregulation and inflammation across cancer and neurodegeneration, with particular emphasis on RNA signaling networks, exosomal communication, and targeted RNA-based therapeutics. Collectively, advances in understanding the RNA–inflammation axis may reveal new opportunities for precision diagnostics and next generation therapeutic interventions. Full article

Salmonella is a globally significant foodborne intracellular pathogen, and invasive salmonellosis poses a major global public health threat. The NLR family CARD-containing protein 4 (NLRC4) inflammasome, a pivotal cytosolic innate immune sensor, specifically recognizes Salmonella flagellin and type III secretion system (T3SS) components via the NAIP (NLR family apoptosis inhibitory protein) family. Upon activation, it triggers pyroptosis, pro-inflammatory cytokine release, and infected intestinal epithelial cell extrusion, serving as a central pathway for host defense against Salmonella colonization and systemic spread. This work systematically summarizes the structural composition, activation mechanisms, post-translational modifications, and regulatory protein network of the NLRC4 inflammasome, and highlights the molecular mechanisms by which Salmonella evades NLRC4 surveillance through multiple strategies: transcriptional downregulation of immunogenic ligands, structural modification of T3SS components, secretion of effector proteins, and chemotaxis-virulence synergy. A comprehensive delineation of the co-evolutionary arms race between Salmonella and the NLRC4 inflammasome provides an integrated mechanistic framework for understanding host–pathogen immune interplay. Deciphering the mechanisms of bacterial immune evasion on this basis holds critical importance for identifying novel anti-infective targets and advancing translational preventive and therapeutic strategies against salmonellosis. Full article

Heparin-binding protein (HBP) is an activation-dependent neutrophil granule protein involved in innate immune activation, endothelial barrier disruption, and inflammatory tissue injury. Although HBP has been extensively investigated in infectious diseases, particularly sepsis, its potential relevance to transplantation has only recently attracted attention. Several post-transplant complications, including infection, ischemia–reperfusion injury (IRI), microvascular dysfunction, and allograft rejection, share common pathological features such as neutrophil activation, endothelial injury, and excessive inflammatory amplification, suggesting a possible mechanistic role for HBP. This review summarizes the current understanding of HBP biology and evaluates its potential contribution to transplant-associated complications. We also discuss the feasibility of using HBP as an early biomarker for infection surveillance, inflammatory risk stratification, and graft injury monitoring. Furthermore, emerging therapeutic approaches targeting HBP or HBP-mediated vascular inflammation, including neutralizing antibodies, heparin derivatives, and albumin, are critically assessed. While experimental studies have provided preliminary evidence supporting HBP-targeted intervention, clinical validation in transplant populations remains insufficient. Future studies should define the temporal dynamics, cellular sources, and context-specific effects of HBP after transplantation. Collectively, available evidence indicates that HBP may serve as a potential biomarker and therapeutic target, but its clinical application requires further validation through mechanistic and prospective studies. Full article

Background: Immune modulation is central to cutaneous melanoma, and antitumor immune responses may be influenced by host genetic background. This study investigated the association between the interleukin-1β gene (IL1B) exon 5 synonymous single-nucleotide polymorphism rs1143634 (+3954 C>T) and cutaneous melanoma in a Northeast Italian case–control cohort. Methods: The study included 133 Caucasian patients with cutaneous melanoma and 945 healthy controls from Northeast Italy. The rs1143634 polymorphism was genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP). Results: Compared with healthy controls, melanoma patients showed higher frequencies of the rs1143634 T allele [27.8% vs. 20.3%; odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.13–2.03, p = 0.005] and CT genotype (43.6% vs. 31.6%; OR = 1.67, CI = 1.16–2.42, p = 0.006), whereas the CC genotype was less frequent (50.4% vs. 63.9%; OR = 0.57, CI = 0.40–0.83, p = 0.003). TT + CT genotypes were more frequent among non-metastatic melanoma cases than controls (OR = 2.23, CI = 1.37–3.64, p = 0.001), but the direct comparison between metastatic and non-metastatic cases was not statistically significant. Among melanoma patients, TT + CT carriers showed an inverse association with Stage IV disease (OR = 0.38, CI = 0.15–0.94, p = 0.036) and a positive association with upper-limb melanoma (OR = 9.10, CI = 1.11–75.0, p = 0.040); these subgroup findings were exploratory because of small numbers and wide confidence intervals. Conclusions: These preliminary findings suggest a possible association between IL1B rs1143634 T allele carriage and cutaneous melanoma susceptibility in this cohort. The Stage IV and upper-limb observations should be considered hypothesis-generating. Larger independent studies, correction-aware statistical designs, cytokine or expression measurements, and functional validation are needed to confirm these observations and clarify their biological relevance. Full article

Background/Objective: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps that is characterized by abundant eosinophilic infiltration within nasal polyps. Tuft cells are epithelial chemosensory cells that are present in the normal respiratory tract and activate group-2 innate lymphoid cells through their secretion of interleukin-25 and prostaglandin (PG) D₂. ECRS is also characterized by the activation of group-2 innate lymphoid cells; however, the involvement of tuft cell-derived PGD₂ in this process remains unclear. Methods: We selected consecutive patients with and without ECRS who underwent biopsy or surgical resection. Dual immunohistochemical analyses were performed to determine the presence of tuft cells producing PGD₂, using POU class 2 transcription factor (POU2F3), a specific tuft cell marker, and hematopoietic prostaglandin D synthase (H-PGDS). Results: The cohort included 52 and 14 patients with and without ECRS, respectively. The number of total POU2F3-positive tuft cells (POU2F3⁺/H-PGDS⁺ and POU2F3⁺/H-PGDS⁻) was significantly higher in the ECRS group vs. the non-ECRS one (p < 0.0001). Moreover, the ratio of POU2F3-positive tuft cells expressing H-PGDS [POU2F3⁺/H-PGDS⁺/(POU2F3⁺/H-PGDS⁺ + POU2F3⁺/H-PGDS⁻)] was also significantly higher in the ECRS group vs. the non-ECRS one (p = 0.0084). Conclusions: These results suggest that tuft cells present in the context of ECRS may serve as a potential source of PGD₂, thus involving to the amplification of type 2 inflammation. Full article

Background/Objectives: Extracellular vesicles (EVs) participate in tumor progression and immune regulation through the transfer of bioactive molecules. Although tumor-derived EVs are generally considered to promote metastasis, accumulating evidence suggests that their functions vary according to the biological characteristics of their cells of origin. This study investigated the mechanisms underlying the anti-metastatic effects of EVs derived from Nanog-overexpressing melanoma cells (Nanog⁺F10-EVs). Methods: Nanog⁺F10-EVs were isolated and characterized by EV marker expression. Their anti-metastatic activity was evaluated using melanoma liver metastasis models in Rag2-deficient and macrophage-depleted mice. Differential miRNA expression analysis was performed to identify candidate functional mediators. Functional studies were conducted using miR-19a-3p-overexpressing cells and EVs. Results: Nanog⁺F10-EVs significantly suppressed melanoma metastasis. Rag2 deficiency only modestly affected this activity, whereas macrophage depletion abolished the anti-metastatic effect, suggesting a predominant role of innate immunity. miRNA profiling identified miR-19a-3p as a candidate mediator enriched in Nanog⁺F10-EVs. Despite promoting tumor cell proliferation and migration, miR-19a-3p-enriched EVs partially reproduced anti-metastatic activity. Macrophage marker analysis suggested that these effects were not fully explained by classical M1/M2 polarization. Conclusions: Nanog⁺F10-EVs may suppress metastasis through macrophage-dependent innate immune regulation potentially mediated by miR-19a-3p and are consistent with a model of preemptive immune education. Full article