Search Results (9,748)

Background/Objectives: Brucella is a major global One Health threat, causing an estimated 2.1 million human infections and substantial livestock losses annually, with no vaccine currently available for humans, underscoring the urgent need for a safe and effective vaccine. Methods: Employing a reverse vaccinology approach, a novel 175-mer multiepitope vaccine (Mvax) targeting Brucella FrpB was computationally designed in this study, incorporating two B-cell, two MHC class I (MHC-I), and three MHC class II (MHC-II) epitopes selected for their high predicted antigenicity, safety, and IFN-γ-inducing potential. Human β-defensin-3 (hBD3) was fused to the N-terminus as an adjuvant, followed by comprehensive in silico evaluation of the construct. Results: Population coverage analysis predicted 99.59% global MHC class I/II coverage for selected epitopes. In silico analyses predicted that Mvax has high solubility (Protein-SOL score: 0.808), a high antigenicity score (VaxiJen: 1.06), and a negative GRAVY index (−0.881), indicating favorable predicted physicochemical characteristics. iMODS, CABS-Flex 3, and molecular dynamics simulations suggested theoretical stability trends for the modeled vaccine complexes. C-ImmSim immune simulations further predicted elevated Th1 cell populations and associated cytokines (IL-12, IFN-γ, IL-2) following both single and multiple simulated Mvax exposures. Conclusions: The computational analyses described here provide a theoretical modeling basis for an antivirulence multi-epitope vaccine design against human brucellosis, with predicted metrics and simulated immune responses requiring empirical validation. Full article

Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but may become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently characterized. We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to stimulation of Toll-like receptors (TLR) were measured. We further examined whether TRIM influenced susceptibility to HIV infection in MDMs derived from monocytes exposed to extracellular vesicles carrying the HIV-1 Nef protein (Nef EVs). Baseline IL-6 production did not differ between unstimulated MDMs from PLWH and uninfected controls. Although sex-associated differences were initially observed, these effects were no longer significant after adjustment for infection duration. IL-6 responses following TLR2 and TLR7 stimulation, but not TLR4 stimulation, were significantly amplified in PLWH-derived MDMs, consistent with a trained phenotype. Similar trends were observed in sex-stratified analyses but did not reach statistical significance. The magnitude of unstimulated IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting over time. Despite heightened inflammatory responsiveness, TRIM did not reduce susceptibility to HIV infection in Nef EV-exposed MDMs, indicating functional maladaptation rather than protective priming. These findings provide evidence of maladaptive TRIM in PLWH, characterized by preserved basal cytokine output but exaggerated inflammatory responses to innate immune stimulation without antiviral benefit. The association with infection duration supports progressive innate immune reprogramming as a contributor to HIV-associated inflammation. No statistically significant differences in trained immune responses were observed between male and female PLWH after accounting for duration of infection. Further studies are needed to define the mechanisms underlying this maladaptation and its clinical consequences. Full article

Bipolar affective disorder (BD) is a severe mental illness characterized by recurrent episodes of mania, hypomania, and depression, accompanied by progressive neurobiological changes that go beyond the classical concepts of neurotransmitter dysregulation. Increasing evidence points to the key role of the interaction between inflammatory processes, mitochondrial dysfunction, and disturbances within neural networks in the pathogenesis, course, and treatment response of BD. Neuroinflammatory processes, including elevated levels of pro-inflammatory cytokines, chemokines, and microglial activation, are consistently reported in patients with BD and linked to cognitive impairment, accelerated neuroprogression, and treatment resistance. At the same time, mitochondrial abnormalities—such as impaired oxidative phosphorylation, excessive production of reactive oxygen species, and disturbances in calcium homeostasis—contribute to oxidative stress, synaptic dysfunction, and increased neuronal vulnerability, forming the biological substrate of mood instability. Findings from neuroimaging studies provide consistent evidence of structural and functional alterations within the cortico-limbic networks regulating emotions, including the prefrontal cortex, anterior cingulate cortex, amygdala, and hippocampus. Importantly, a growing number of studies demonstrate correlations between neuroimaging changes and inflammatory and metabolic biomarkers, making it possible to link molecular pathology with dysfunctions at the level of neural networks. The use of multimodal methods—encompassing structural and functional magnetic resonance imaging, spectroscopy, and molecular analyses—allows for a more precise explanation of these complex interactions and the identification of biomarkers of clinical states, progression, and treatment response. This review synthesizes current knowledge on the molecular and neuroimaging correlates of BD, emphasizing the interdependence of inflammatory processes, mitochondrial function, and neural networks. The integration of molecular biomarkers with imaging-based phenotyping opens new perspectives for precision medicine in BD. Full article

Neuroinflammation plays a dual role in brain health supporting defense and repair, but causes neurotoxicity when persistent. Microglia and astrocytes coordinate these responses through cytokine signaling and extracellular vesicles (EVs), though their vesicle-mediated communication remains unclear. This study investigated whether EVs from activated microglia (ABEVs) influence astrocyte polarization and inflammatory signaling. BV-2 microglial cells were activated with lipopolysaccharide (LPS), and microvesicle (ABMVs) and exosome (ABEXs) EVs were isolated via sequential ultracentrifugation. Primary mouse astrocytes were treated with LPS, ABMVs, or ABEXs, and expression of reactive astrocyte markers (C3, Serpina3n, S100a10, Sphk1) and inflammatory mediators (Lcn2, Il-1β, Ccl2, Ccl5, Cxcl10) was quantified, and EV protein cargo was analyzed by mass spectrometry and proteomics. LPS-treated astrocytes exhibited increased C3 and Serpina3n and decreased S100a10, consistent with reactive polarization. ABEXs mimicked this effect, significantly inducing C3, Serpina3n, and Sphk1, whereas ABMVs had a weaker influence. ABEXs also upregulated Lcn2 and Il-1β, partially reproducing microglial inflammatory effects. Proteomic profiling revealed marked cargo differences: ABEXs exhibited 16 upregulated proteins linked to NOD-like receptor signaling compared to non-activated BEXs, and 165 proteins associated with ribosome biogenesis and spliceosome pathways compared to ABMVs, indicating subtype-specific signaling potential. Collectively, our findings demonstrate that microglia-derived EVs modulate astrocytic polarization and cytokine profiles in a cargo-dependent manner, emphasizing their importance in interglial communication and revealing novel targets for neuroinflammatory modulation. Full article

Interleukin-6 (IL-6) is a multifunctional cytokine with an essential role in immunity, inflammation, and cancer. Produced by immune, stromal and epithelial cells in response to infection or tissue stress, IL-6 regulates immune responses, acute-phase proteins (including serum amyloid A and C-reactive protein), hematopoiesis, and tissue remodeling. These effects are mediated via classical and trans-signaling pathways, which activate key intracellular cascades such as JAK/STAT3, MAPK, and PI3K/AKT. Accumulating evidence implicates dysregulated IL-6 signaling in both oncologic and infectious diseases, where it contributes to disease progression, immune evasion, and therapeutic resistance. This review aims to critically examine the role of IL-6 as a biomarker and therapeutic target in these two major clinical contexts: in cancer, IL-6 levels reflect tumor burden, prognosis, and therapy resistance in both adult and pediatric patients; in infectious diseases, circulating IL-6 may support early diagnosis and risk stratification, particularly in vulnerable pediatric populations. By integrating molecular mechanisms with clinical evidence, this review highlights IL-6 as a unifying biomarker linking inflammation, infection, and malignancy. It also addresses current limitations, including assay variability, lack of standardized reference ranges, especially in children, and challenges in clinical implementation. Full article

Weaning is a critical developmental stage in puppies often accompanied by gastrointestinal disturbances and empiric antibiotic use. This double-blind, placebo-controlled trial evaluated the safety and efficacy of two canine milk-derived probiotic strains, Lacticaseibacillus rhamnosus CECT 30021 and Lactiplantibacillus plantarum CECT 30022, in recently weaned Labrador Retriever puppies. Forty-nine healthy puppies were enrolled and allocated to receive a daily capsule containing either strain alone, a combination of both, or placebo for six weeks, followed by a six-week observation period. Probiotic supplementation was well tolerated, and clinical, hematological, and biochemical parameters remained within normal ranges. Compared with placebo, the probiotic-treated puppies experienced fewer gastrointestinal infections and required less antibiotic therapy. Supplementation helped maintain normal fecal consistency, prevented increases in fecal calprotectin and inflammatory cytokines, and produced significantly higher fecal short-chain fatty acid concentrations. Systemically, probiotic intake was associated with lower serum cortisol, IL-8, TNF-$\alpha$, and cholesterol, and stronger antibody responses to vaccination. Probiotic-supplemented puppies also showed faster weight gain during treatment, and this difference persisted after supplementation ended. Overall, these findings indicate that both strains, administered individually or in combination, safely support gastrointestinal, metabolic, endocrine, and immunological health in Labrador Retriever puppies during weaning and may help reduce the need for antibiotics. Full article

Sepsis remains a leading cause of global mortality and is characterized by a dysregulated host immune response to infection. Early deaths often result from hyperinflammation and organ dysfunction, whereas late-stage mortality is increasingly attributed to sepsis-induced immunosuppression, leading to secondary infections and viral reactivation. Challenges persist in the identification and management of sepsis-induced immunosuppression, including the lack of standardized immune monitoring methods, the absence of reliable immune biomarkers to guide therapy, and the limited success of immunomodulatory therapies in clinical trials. This review comprehensively summarizes the pathophysiology of sepsis-induced immunosuppression, encompassing immune cell apoptosis and exhaustion, the expansion and activation of immunomodulatory cells, metabolic reprogramming, epigenetic alterations, and iatrogenic factors. We also discuss current diagnostic challenges and explore emerging immunomodulatory strategies, such as cytokine therapies, immune checkpoint inhibitors, and metabolic modulators, as potential approaches to restore immune function. Finally, we highlight the importance of immune phenotyping and individualized precision medicine in the future management of sepsis, and integrating multidisciplinary approaches from mechanistic research to targeted therapies holds promise for improving patient outcomes. Full article

Background/Objectives: Periodontitis is a chronic inflammatory disease with marked inter-individual heterogeneity and well-established links to cardiometabolic and other systemic conditions. Conventional clinical diagnostics remain indispensable. However, they provide limited real-time insight into molecular activity and host-response biology. This review aimed to synthesize recent advances in point-of-care diagnostics and emerging molecular biomarkers relevant to periodontal disease and its systemic associations. Methods: We performed a state-of-the-art narrative review of literature published between 2018 and 2026. The focus was on point-of-care biosensing technologies and molecular biomarkers assessed in oral and related biological matrices. These included saliva, gingival crevicular fluid, blood, and dental plaque. Evidence was prioritized based on analytical performance, clinical validity, and translational readiness. Results: Substantial progress has been made in multiplex optical and electrochemical point-of-care platforms. These include microfluidic systems and early intraoral wearable sensors. Such technologies enable quantification of host-response proteins, including MMP-8, cytokines, and chemokines. In parallel, omics-derived biomarkers are emerging as clinically informative adjuncts for diagnosis and monitoring. MicroRNAs, cell-free DNA, extracellular vesicle–derived signals, proteomic profiles, and microbiome classifiers demonstrate promising discrimination. They also provide mechanistic links to systemic inflammation. Clinical translation remains limited by study heterogeneity, spectrum bias, and insufficient external validation. Conclusions: Near-term clinical value lies in adjunctive risk stratification and longitudinal disease monitoring. Replacement of conventional periodontal examination is not currently justified. Meaningful clinical and public-health impact will require standardized disease definitions. Harmonized sampling and reporting protocols are essential. Multicenter validation across comorbidity strata is needed. Regulatory-grade evidence must be generated for in vitro diagnostics and artificial intelligence software classified as medical devices. Full article

Controlled local hyperthermia supports postoperative wound healing in liver surgery by stimulating metabolism, angiogenesis, and immune responses through the induction of heat shock proteins (HSPs) and modulation of Damage-Associated Molecular Patterns (DAMPs). This study evaluates the impact of thermal modulation on immune processes during abdominal wound repair, specifically analyzing the role of HSPs and immune activation pathways. A narrative review of the literature from 2010 to 2025 was conducted to summarize molecular mechanisms regarding temperature, HSP activation, cytokine expression, and DAMPs, excluding studies conducted solely in animal models. The results indicate that precise local hyperthermia in postoperative abdominal wounds activates HSPs as well as inflammasome and Toll-like receptor (TLR) pathways, modulating immune and cytokine responses depending on the type and depth of tissue injury. Consequently, such thermoimmunomodulation stabilizes immune cell functions, optimizes the balance between inflammation and regeneration, and minimizes the risk of postoperative complications to support effective wound healing. Full article

Background/Objectives: Dendritic cells (DCs) are key regulators of immune responses in cardiovascular disease, yet their role in platelet homeostasis and thrombopoiesis remains incompletely understood. We previously demonstrated that chronic depletion of CD11c⁺ cells accelerates atherosclerotic plaque development. The objective of this study was to determine whether sustained loss of CD11c⁺ cells alters platelet production and systemic inflammatory signaling under atherogenic conditions. Methods: CD11c-DTR bone marrow chimeric mice on ApoE⁻/⁻ background were generated and fed a high-cholesterol diet. CD11c⁺ cells were depleted by repeated diphtheria toxin administration over six weeks. Circulating platelet counts were quantified by automated hematology analysis. Systemic inflammatory changes were assessed using serum cytokine and chemokine profiling, and serum thrombopoietin (TPO) levels were measured by ELISA. Results: Chronic CD11c⁺ cell depletion resulted in a significant increase in circulating platelet counts in ApoE⁻/⁻ mice. Serum cytokine profiling revealed broad inflammatory remodeling, including increased levels of cytokines associated with megakaryopoiesis and platelet activation, such as IL-4, MCP-1, CXCL9, IL-16, and IL-1α. In parallel, serum TPO levels were significantly elevated following CD11c⁺ cell depletion. Conclusions: In the specific context of hyperlipidemic CD11c-DTR bone marrow chimeric mice, these findings demonstrate that loss of CD11c⁺ cells is associated with a pro-thrombopoietic shift, elevated platelet counts, and systemic inflammatory changes. Our data identify a CD11c⁺ cell–TPO–platelet axis linking immune regulation to platelet homeostasis and thrombo-inflammatory signaling under these specific atherogenic conditions. Full article

COVID-19 and influenza A (FluA) cause severe respiratory infections in elderly patients, with cytokine dysregulation playing a central role. Direct comparative data in older adults remains limited. We aimed to characterize cytokine dynamics and their prognostic value in hospitalized elderly patients with COVID-19 vs. FluA. We performed a prospective cohort study including adults ≥ 60 years hospitalized with respiratory failure due to COVID-19 or FluA between March 2023 and March 2024. Serum IL-1β, IL-6, IL-10, IL-17A, IL-34, MCP-1, and CXCL10 were measured on Day 1 and Day 5 of hospitalization using Luminex^®. Cytokines and associations with non-invasive ventilation (NIV) were assessed by ROC analysis and multivariate logistic regression. 83 patients were included (39 COVID-19, median age 79 years; 44 FluA, median 77 years). At Day 1, COVID-19 exhibited significantly higher IL-6, IL-10, and CXCL10; FluA showed an attenuated cytokine response. At Day 5, cytokines declined in both groups. Baseline IL-6 independently predicted NIV (adjusted OR 3.02), whereas higher MCP-1 was associated with reduced NIV requirement. Early cytokine differences between COVID-19 and FluA are evident in elderly patients, but values converged by Day 5. IL-6 remains an informative early predictor of respiratory deterioration; MCP-1 may reflect a regulated innate response. Full article

Background/Objectives: Silicosis is a chronic disease caused by long-term exposure to high levels of silica dust, which leads to extensive nodular fibrosis in the lungs. The disease is currently a serious occupational health hazard globally. Xuanfei Baidu decoction (XFBD) is a mature Chinese herbal medicine in China that has shown anti-inflammatory and anti-fibrotic effects in mouse experiments, making it a promising candidate for addressing the persistent inflammation and fibrosis in silicosis. Methods: Silicosis was induced in male C57BL/6J mice using crystalline silica (CS). XFBD’s early anti-inflammatory role was verified in vitro in peritoneal macrophages (PMs) and in vivo in silicosis mice, while its late anti-collagen deposition and anti-fibrotic activities were further investigated. Results: In vitro, XFBD effectively inhibits the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in CS-induced lipopolysaccharide (LPS)-primed PMs, decreases the release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), and modulates the phenotypic transition of macrophages from the M2 to the M1 phenotype. In vivo studies further validated that XFBD significantly downregulates the expression of NLRP3 and Cleaved-Caspase-1 proteins in the lung tissues of mice afflicted with silicosis. Additionally, XFBD enhanced pulmonary function, inhibited collagen deposition and pulmonary fibrosis in silicosis mice, and reversed epithelial–mesenchymal transition (EMT) by regulating key EMT-related proteins to slow fibrosis. Conclusions: The beneficial effects of XFBD on CS-induced pulmonary fibrosis can be attributed to the induction of macrophage polarization-mediated anti-inflammatory responses during the early stage of fibrotic development, as well as its anti-collagen deposition and anti-fibrotic activities during the intermediate stage of fibrotic development. This study provides preclinical evidence supporting XFBD as a promising candidate for prevention or adjunctive therapy, and its multi-target, time-phase mechanism offers a novel rationale and theoretical foundation for the development of new strategies against silicosis. Full article

Atrial fibrillation (AF) is the most common cardiac arrhythmia responsible for increased risk of a stroke and sudden death. Right heart disease (RHD), characterized by myocardial dysfunction and structural alteration affecting the right ventricle and the right atrium, is recognized as an important risk factor for AF. Inflammation and cardiac fibrosis emerge as arrhythmogenic pathophysiological events commonly occurring in most diseases responsible for cardiac arrhythmias and AF. However, no commercially available anti-inflammatory drugs were shown to irreversibly cure AF. Hence, more investigations are required to identify the key inflammatory and fibrosis agents involved in arrhythmogenesis. In this review, we explore (i) the recent evidence of myocardial, and especially atrial, inflammation in RHD, and (ii) the relevance of targeting inflammatory and anti-inflammatory cytokines in future strategies, combined with current AF management, in RHD. Full article

Background: Chronic inflammatory enteropathies (CIEs) in dogs are multifactorial disorders characterized by mucosal immune dysregulation, compromised epithelial barrier function, and increased exposure to microbial components such as lipopolysaccharide (LPS). The resulting oxidative stress and inflammation contribute to local and systemic pathology. Objective: This study aimed to evaluate the immunomodulatory and antioxidant effects of three naturally occurring flavonoids—quercetin, luteolin, and grape seed extract oligomeric proanthocyanidins (GSOPs)—in LPS-stimulated canine duodenal explants. Methods: Duodenal tissue samples were cultured in vitro and challenged with LPS derived from Escherichia coli and Salmonella enterica. Explants were co-incubated with flavonoid compounds, and endpoints included evaluation of histological architecture, inflammatory cytokine production, and reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. Results: All three flavonoids attenuated LPS-induced mucosal inflammation and ROS production to varying degrees. In addition, GSOPs significantly reduced RNS levels under both basal and LPS-stimulated conditions. Quercetin and luteolin demonstrated pronounced downregulation of TNF-α, while both compounds also reduced IL-6 concentrations under non-stimulated conditions. These effects support the hypothesis that flavonoids can mitigate both inflammatory and oxidative responses under conditions relevant to CIE. Conclusion: Quercetin, luteolin, and GSOPs show promising in vitro efficacy in modulating key mechanisms implicated in canine CIE. Their multimodal actions highlight their potential as adjunctive nutraceuticals for the management of CIE in dogs. However, further in vivo validation is warranted. Full article

Background/Objectives: Maresin-1 (MaR1), a specialized pro-resolving mediator (SPM) derived from omega-3 fatty acids, has demonstrated potent anti-inflammatory and pro-resolving properties. However, its effects on depression-like behaviors and the associated dynamics of neuroinflammation, particularly in the context of chronic stress, are not yet fully understood. This study aimed to investigate the therapeutic potential of MaR1 in a chronic unpredictable stress (CUS) model and to monitor its dynamic effects on neuroimmune activity using longitudinal in vivo imaging. Methods: Adolescent male C57BL/6J mice were subjected to a 5-week CUS protocol. Mice exhibiting stable anhedonia were randomized to receive intraperitoneal injections of either MaR1 (5 µg/kg) or vehicle every other day for 4 weeks. During this period, CUS procedures were maintained. Depression-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Dynamic changes in neuroinflammation were monitored via longitudinal [18F]DPA-714 positron emission tomography (PET) scans at baseline and after 2 and 4 weeks of treatment. Ex vivo analyses included immunofluorescence quantification of hippocampal microglia (ionized calcium-binding adaptor molecule 1, Iba1), astrocytes (glial fibrillary acidic protein, GFAP), and 18 kDa translocator protein (TSPO) co-expression, alongside quantitative polymerase chain reaction (qPCR) and Western blotting for inflammatory markers (IL-1β, IL-4, TSPO). Results: MaR1 treatment selectively alleviated depression-like behaviors, significantly reversing CUS-induced anhedonia in the SPT and improving locomotor activity, while its effect on despair-like behavior (TST) was not statistically significant. Longitudinal PET imaging revealed a biphasic neuroimmune response, characterized by an initial increase in [18F]DPA-714 standardized uptake value (SUV) at 2 weeks, followed by a return toward baseline at 4 weeks. Histologically, MaR1 reversed CUS-induced hippocampal microglial loss, resulting in a rebound of microglial numbers, and normalized astrocytic activation. At the molecular level, MaR1 dynamically modulated cytokine expression, culminating in a significant upregulation of the pro-resolving marker IL-4 and TSPO at 4 weeks. Conclusions: These findings indicate that Maresin-1 treatment is associated with behavioral improvement and dynamic modulation of glial activity and TSPO PET signals in the hippocampus. This study highlights the value of TSPO PET imaging for monitoring dynamic glial changes during therapeutic intervention and provides supportive evidence for targeting neuroimmune pathways in depression. Full article