Search Results (24,203)

Copper is a crucial cofactor that sustains multiple cellular electron-transfer reactions, making it an essential element for life. However, cytotoxic levels of copper can cause structural damage and cell death through the production of reactive oxygen species (ROS) and nonspecific attacks on proteins. Moreover, immune cells, including neutrophils and macrophages, accumulate copper to induce oxidative bursts that kill engulfed pathogens. Therefore, a well-regulated copper homeostasis system is required for the human commensal fungus Candida albicans to thrive in extreme host environments. Remarkably, C. albicans exhibits higher copper tolerance than the nonpathogenic model yeast Saccharomyces cerevisiae, suggesting the presence of a specific copper tolerance mechanism that supports its adaptability to copper stress. Ndt80 is a versatile transcription factor that regulates several biological processes in C. albicans, ranging from morphological control to drug resistance. This study further reveals that Ndt80 may contribute to copper tolerance by regulating copper transporters and copper-dependent superoxide dismutases (Sods). Additionally, RNA sequencing and complementary approaches uncovered the involvement of Ndt80 in plasma membrane integrity and mitochondrial respiration under copper stress, further linking Ndt80 to copper tolerance. Together, these results broaden our understanding of Ndt80 functions and provide new insights into copper tolerance in C. albicans. Full article

Salmonella enterica infection remains a major threat to poultry health and food safety, largely due to its ability to invade the intestinal epithelium, modulate host immunity, and persist intracellularly. Curcumin, a bioactive phytochemical, has shown promising antimicrobial and immunomodulatory potential; however, its precise molecular interplay with host and pathogen systems remains unclear. An integrated computational pipeline was applied, combining target prediction, host immune network construction, Salmonella virulence interaction analysis, STRING-based PPI mapping, KEGG/GO enrichment, and molecular docking validation. Host immune hub genes and Salmonella virulence regulators were identified, followed by docking of curcumin to key host (AKT1, STAT3, TNF) and pathogen proteins (invA, phoP, ssrB). Host network analysis revealed enrichment in the PI3K–AKT, NF-κB, FoxO, and IL-10 signaling pathways, indicating roles in epithelial protection, immune regulation, inflammation suppression, and antioxidant defense. Salmonella virulence hubs were primarily associated with epithelial invasion, Type III secretion, intracellular survival, and global virulence reg-ulation. Docking analysis demonstrated a strong binding affinity of curcumin toward AKT1 (−7.4 kcal/mol), STAT3 (−6.5 kcal/mol) and TNF (−5.8 kcal/mol), supporting host immunomodulation and epithelial protection. Simultaneously, curcumin showed notable affinity for phoP (−6.8 kcal/mol), invA (−6.3 kcal/mol), and ssrB (−5.8 kcal/mol), suggesting the potential suppression of virulence signaling, invasion machinery, and intracellular persistence. This integrated host–pathogen systems analysis demonstrates that curcumin exerts a dual regulatory effect by enhancing host immune protection while concurrently disrupting Salmonella virulence mechanisms. These findings provide mechanistic insight supporting curcumin as a promising natural therapeutic candidate for controlling Salmonella infection in broilers. Full article

A phage is a virus that targets bacteria with high precision. While phage therapy provides a targeted alternative to broad-spectrum antibiotics, it is not completely free from the challenges of antimicrobial resistance, as phages can facilitate the horizontal transfer of resistance genes through transduction and promote the growth of phage-resistant strains. Nonetheless, within the One Health framework, the strategic use of phages remains a vital and promising tool for addressing the global antimicrobial resistance crisis. This paper reviews current research on phage therapy for gastrointestinal diseases such as cirrhosis, enteritis, and Helicobacter pylori infection. It also details how phages help regulate gut microecological balance and discusses how phage dysbiosis can lead to innate immune dysfunction and worsen conditions like inflammatory bowel disease. The review summarizes both the therapeutic potential and limitations observed in clinical trials and fundamental studies. Transitioning from laboratory research to clinical practice is hindered by multiple complex challenges, including the stomach’s extreme acidity, physical entrapment by the intestinal mucus layer, the rapid co-evolution of bacterial resistance, and ecological risks associated with temperate phages. To overcome challenges like gastrointestinal barrier tolerance and address ethical, technical, and practical hurdles for clinical use, the paper outlines treatment strategies for specific conditions and highlights future directions, providing guidance for employing phages in digestive system disease management. These future innovations focus on integrating artificial intelligence-driven precision matching, advanced bioengineering for durable delivery systems, and multimodal combination therapies to safely modulate the intestinal microecology. Full article

Probiotics are commonly applied to maintain the balance of gut microbiota and regulate the intestinal metabolic function of companion animals. In the present study, complex probiotics (Bacillus coagulans SNZ-1969, Bacillus subtilis, and Bacillus licheniformis) were added into the basal diet of domestic cats to investigate their influence on the intestinal microbiome and metabolic characteristics. Results revealed that the alpha diversity of the gut microbiota in the probiotic group was enhanced when compared to the control group. The beta diversity of the gut microbiota was also altered by the oral consumption of the complex probiotics. Compared to the control group, the relative abundance of beneficial microbes (such as Clostridium, Bacteroides, Phocaeicola, and Ruminococcus) in the probiotic group was enhanced, while the relative abundance of opportunistic pathogens (such as Escherichia, Gallibacter, Corynebacterium) was decreased. Additionally, the intestinal metabolic characteristics of domestic cats were also changed. The metabolomic analysis identified 408 differential metabolites between the two groups, and the KEGG function pathway analysis proved that the dominant pathway related to the differential metabolites were the amino acid metabolism, lipid metabolism, carbohydrate metabolism, energy metabolism, endocrine system, digestive system, immune system, and other metabolic pathways. Spearman’s correlation analysis revealed that the beneficial microbes had positive correlations with the differential metabolites. In conclusion, the current study demonstrated that oral administration of complex probiotics could regulate overall health and well-being in domestic cats through modulating the gut microbiome and metabolic characteristics. Full article

Background/Objectives: Umami peptides enhance flavor and contribute to appetite regulation (satiety) and metabolic health. By signaling to the orbitofrontal cortex, umami has been shown to improve cognitive function in Alzheimer’s disease dementia. This taste boosts the immune system and induces saliva secretion. However, the molecular mechanisms linking umami peptides to systemic physiology remain poorly understood. This study provides the first integrated analysis of neurological, immunological, and endocrinological pathways activated by umami peptides. Methods: Novel umami peptides were identified using machine-learning and deep-learning analyses from a library of marine-derived bioactive peptides. T1R1-T1R3 heterodimer is the dominant receptor for umami taste transmission in humans, expressed on taste cells, intestinal cells, and hypothalamic tanycytes. Molecular docking confirmed the binding of novel ligands to the T1R1-T1R3 receptor complex. New candidates and experimentally validated umami peptides, identified by sensomics approaches from tauco, chicken soup, pufferfish, and dry-cured ham, were analyzed using gene ontology. Results: The functional enrichment analysis revealed crosstalk among key signaling processes, including glutamatergic and opioidergic pathways. In addition to the role of µ1 opioid receptor (OPRM1), hub gene intersections highlight cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and the anorexigenic pro-opiomelanocortin (POMC) neurons as potential regulators of the gut–brain axis in satiety signaling. Chemokine-encoding genes, melanin-concentrating hormone (MCH), oxytocin (OXT), and neurotensin (NTS) were other key target genes. Conclusions: The identified targets reveal the coordinated crosstalk between peripheral and central umami signaling that may contribute to the regulation of feeding behavior, satiety, cognition, memory, learning, and immune function. These network-based insights generate hypotheses and guide the design of nutritional and drug-like effectors for metabolic and cognitive health. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by early metastasis, dense desmoplastic stroma and a profoundly immunosuppressive, lymphocyte-depleted tumor microenvironment that severely limits the efficacy of current systemic and immunotherapeutic approaches. Oncolytic viruses (OVs), which selectively replicate in and lyse malignant cells while activating antitumor immunity, have emerged as attractive candidates to convert this “cold” tumor into a more inflamed and therapeutically responsive disease. In this review, we summarize clinical evidence on the main OV platforms evaluated in PDAC, including adenovirus, herpes simplex virus, vaccinia virus, parvovirus and reovirus, with a focus on clinical trials. Across these classes of viruses, intratumoral administration has consistently proven feasible and generally well tolerated, with frequent evidence of viral replication, microenvironmental remodeling and immune activation, but only modest and often transient antitumor responses in small, early-phase cohorts. We then discuss key biological and translational challenges that currently limit OV impact in PDAC, such as systemic delivery in the context of pre-existing antiviral immunity and rapid clearance, penetration through the fibrotic stroma, and rational selection of encoded transgenes to reshape myeloid cell-driven, pro-tumoral inflammation and enhance T-cell recruitment. Finally, we outline future directions for the field, including carrier-cell–based systemic delivery, stroma-targeting or cytokine-armed constructs, and combinatorial strategies with chemotherapy and immune checkpoint blockade, arguing that design refinement, innovative combinations and mechanism-driven trial designs will be essential to unlock the full therapeutic potential of oncolytic virotherapy in PDAC. Full article

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF–immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options. Full article

Background: Intracavernosal platelet-rich plasma (PRP) is increasingly used for erectile dysfunction (ED), despite the absence of standardized biological characterization and clear dose definitions. This systematic review evaluates the clinical efficacy of PRP in ED while integrating emerging immune-centric mechanistic evidence. Methods: Following PRISMA 2020 guidelines, randomized controlled trials (RCTs) and prospective studies (2020–2025) investigating intracavernosal PRP in adult men with ED were identified across major databases. Validated outcomes included International Index of Erectile Function (IIEF-EF or IIEF-5), Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), and penile Doppler parameters. Preclinical data were narratively integrated to contextualize biological plausibility. Results: Fourteen clinical studies met the inclusion criteria (six RCTs, eight prospective cohorts). Across most studies, PRP produced clinically relevant within-patient improvements, and three RCTs demonstrated minimal clinically important difference (MCID) responder rates compared with placebo. However, other trials showed comparable improvements in placebo arms, underscoring substantial contextual effects. Safety was consistently favourable. Marked heterogeneity in blood volume processed (10–120 mL), injected PRP volume (3–12 mL), preparation systems, and session protocols precluded cross-study comparability. Critically, no study reported platelet dose, leukocyte subsets, peripheral blood mononuclear cell (PBMNC) content, or red blood cell contamination. Preclinical models consistently demonstrate that PRP restores erectile function through angiogenic, neuroprotective, and immunomodulatory mechanisms, including CXCL5-mediated monocyte recruitment and M1-to-M2 macrophage polarization. Conclusions: Intracavernosal PRP shows promising short-term efficacy signals and a favourable short-term safety profile in mild-to-moderate vasculogenic ED, but current evidence is limited by profound biological and methodological heterogeneity. PRP should be reconsidered as an immune-regenerative intervention requiring dose-defined, composition-defined, and mechanistically informed randomized trials. Interpretation of these findings is constrained by the absence of formal risk-of-bias assessment for non-randomized studies, substantial clinical and biological heterogeneity across trials, and the lack of standardized PRP characterization. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by several factors, including immune system imbalance, impairment of the epidermal barrier, and alterations in the composition of the gut and skin bacterial and fungal microbiota. This study combines metagenomic sequencing and culture-based methods to explore the impact of probiotic supplementation on the cutaneous microbiota and mycobiota of AD patients. Twenty-five adults diagnosed with AD were enrolled, and skin swabs were analyzed to characterize microbial diversity and load. Culturomic analyses identified 42 bacterial and 6 fungal species, confirming Staphylococcus aureus and Candida parapsilosis as predominant taxa. High-throughput sequencing revealed Staphylococcus spp. and Malassezia spp. as dominant genera, with notable interindividual variability. While probiotic use did not significantly influence bacterial diversity, it was associated with higher richness and evenness in fungal communities, as shown by alpha and beta diversity metrics. Malassezia restricta was more prevalent among probiotic users, whereas Candida parapsilosis and Rhodotorula mucilaginosa were enriched in non-users. These findings indicate an association between probiotic use and differences in the composition and diversity of the skin mycobiota compared with the bacterial microbiota, suggesting that fungal communities may be more responsive to probiotic-associated factors. Integrating metagenomic and culturomic approaches offers valuable insights into the complex interactions among host factors, microbial communities, and probiotic use in AD, paving the way for targeted microbiome-based therapeutic strategies. Full article

Background/Objectives: Sepsis is a leading cause of hospital mortality and represents a time-sensitive medical emergency. Current diagnostic strategies rely on clinical assessment, severity scores, biomarkers, and blood cultures. However, blood cultures require 24–72 h for pathogen identification and demonstrate limited sensitivity, while biomarkers such as procalcitonin and C-reactive protein lack optimal specificity. These limitations support the widespread empirical use of broad-spectrum antibiotics and highlight the need for rapid, sensitive, and culture-independent diagnostic tools. Methods: A narrative literature review was conducted using PubMed and Google Scholar, including 28 studies published over the past 10 years, encompassing observational and preclinical investigations. Current evidence on the application of Raman spectroscopy in sepsis was summarized, with a dual focus on pathogen identification and the assessment of the host response. Results: Raman spectroscopy has demonstrated the ability to detect early molecular alterations in circulating immune cells and mitochondrial redox status, potentially preceding conventional biomarkers. For pathogen identification, Raman techniques have achieved diagnostic accuracies comparable to automated systems, but with significantly shorter turnaround times. Integration with microfluidics, optical tweezers, and deep learning algorithms has further enhanced performance, although these applications remain largely experimental. Conclusions: Despite these promising results, the lack of methodological standardization, spectral overlap among phylogenetically related species, limited large-scale validation, and challenges in interpreting certain spectral signatures remain unresolved. Most available evidence originates from preclinical, single-center, and controlled studies, underscoring the need for prospective multicenter trials and harmonized protocols. Full article

C. burnetii (Cb) is an obligate intracellular bacterial pathogen that replicates within alveolar macrophages following aerosol infection. Unlike most intracellular bacteria, Cb establishes a lysosome-derived replicative niche (Coxiella-containing vacuole or CCV) through the action of its Type IVB secretion system (T4BSS). This system translocates a large repertoire of effector proteins into the host cytoplasm after phagosome acidification. These effectors interfere with diverse signaling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, promoting pathogen survival without triggering robust proinflammatory signaling or host cell death pathways. This effector-triggered immune silencing is particularly unique given the central role of macrophages as innate immune sentinels. In this review, we examine Cb T4BSS effectors that have been characterized as central determinants of innate immunity modulation. We discuss innate immune sensing pathways potentially engaged during infection, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors, inflammasomes, and interferon signaling pathways, and highlight evidence indicating that these pathways are actively suppressed. Emphasis is placed on effector-mediated regulation of NF-κB signaling, type I interferon responses, and inflammasome activation. Finally, we address unresolved questions related to effector-triggered immunity, redundancy in immune suppression, and discrepancies between in vitro and in vivo infection models. Full article

Honey bees rely on a specialized gut microbiota for nutrition, detoxification, and immune function, yet the effects of emerging insecticides on this symbiotic system remain poorly understood. We compared the acute toxicity and short-term gut microbiota responses of Apis mellifera ligustica workers exposed to two insecticides with contrasting toxicity classes: the highly toxic emamectin benzoate-lufenuron (EB-LFR) and the low-toxicity ecdysone agonist RH-5849. EB-LFR was associated with observed reductions in core gut symbionts (Gilliamella, Snodgrassella, Lactobacillus), a transient increase in Bifidobacterium, and the detection of opportunistic taxa such as Serratia marcescens and Enterobacter hormaechei. In contrast, RH-5849 was associated with broad reductions in beneficial bacteria without detectable pathogen emergence, suggesting a more moderate alteration of microbiota composition. Because microbiota analyses were based on single pooled samples per treatment, these results represent exploratory, qualitative insights into early microbial responses. Together with acute toxicity data, the findings suggest that insecticides with contrasting toxicity classes may differentially affect gut microbiota composition in honey bees and highlight the value of incorporating gut microbiota endpoints into pesticide risk-assessment frameworks to better anticipate sublethal effects on pollinator health. Full article

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus responsible for sporadic outbreaks of severe disease with high case fatality rates in South and Southeast Asia. Human infection occurs through spillover from natural reservoirs, primarily fruit bats, or via human-to-human transmission, and is characterized by a broad clinical spectrum ranging from asymptomatic infection to acute respiratory disease and fatal encephalitis. Following entry via ephrin-B2 and ephrin-B3 receptors, NiV exhibits marked endothelial and neuronal tropism, leading to systemic vasculitis, disruption of the blood–brain barrier, and direct infection of the central nervous system. Disease progression is driven by a complex interplay between viral replication strategies and host immune responses. NiV effectively counteracts innate immunity through multiple viral proteins that inhibit interferon signaling, while simultaneously inducing dysregulated inflammatory responses that contribute to tissue damage and multi-organ failure. Neurological involvement represents the most severe manifestation, often resulting in acute or relapsing encephalitis with long-term sequelae among survivors. Despite the severity of the disease, no licensed antiviral therapies or human vaccines are currently available. Therapeutic development has focused on neutralizing monoclonal antibodies targeting viral glycoproteins and small-molecule antivirals that inhibit viral RNA synthesis, both of which show promising results in preclinical models, but remain limited by timing and translational challenges. In parallel, several vaccine platforms—including viral vectors, mRNA-based constructs, and recombinant protein subunits—have advanced to early-phase clinical trials, demonstrating encouraging immunogenicity. Beyond biomedical interventions, effective outbreak containment relies on integrated public health strategies. The “Kerala model” highlights the importance of rapid case identification, isolation, contact tracing, and community engagement within a One Health framework to mitigate transmission and reduce mortality. This review synthesizes the current knowledge on NiV pathogenesis, immune evasion, clinical manifestations, and emerging therapeutic and vaccine strategies, while highlighting critical gaps and future directions for improving the preparedness and response to this high-consequence emerging pathogen. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation. Full article

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood–retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues. Full article