Search Results (2,405)

Glycosylation of surface proteins is a crucial post-translational modification that reflects the activation status of neutrophils, the predominant leukocyte subset in humans and horses. Neutrophils have emerged as active contributors to diseases mediated by the adaptive immune system, such as equine recurrent uveitis (ERU), a sight-threatening disease in horses and a unique model for studying the pathogenesis of autoimmune uveitis in humans. Since changes in surface glycosylation can impact neutrophil function, we were interested in the surface glycosylation landscape on neutrophils from healthy horses and the potential changes in surface glyco-signatures in ERU. Using 35 different plant lectins, we outlined a profile of surface-exposed glycan moieties on equine neutrophils and detected significantly increased O-glycosylation in a diseased state through Jacalin (JAC) binding via flow cytometry. Subsequent molecular weight comparison of JAC pull-down assay data and neutrophil proteomics indicated the surface proteins Integrin beta-2 and CUB domain-containing protein 1 as potential anchors for increased O-glycan levels in ERU. These findings give novel insights into neutrophil surface glycosylation in health and disease and propose O-glycosylation as a possible biomarker for autoimmune uveitis. Full article

Ischemic heart disease remains the leading cause of death despite substantial advances in diagnosis, revascularization therapies, and risk-factor control. Beta-adrenergic receptor blockers (Beta-Blockers, BBs), long used to control heart rate, blood pressure, and reduce arrhythmic risk, may also confer cardioprotection through mechanisms beyond hemodynamic unloading. This review integrates an extensive range of preclinical, translational, and clinical studies to present a comprehensive overview of the cardioprotective effects of BBs in the context of myocardial ischemia and reperfusion injury. Mechanistic domains include modulation of redox homeostasis, attenuation of inflammation and neutrophil activation, preservation of mitochondrial integrity and anti-apoptotic signaling, improvement of endothelial function, and stabilization of calcium handling. Third-generation compounds, carvedilol and nebivolol, demonstrate additional antioxidant and vasodilatory benefits compared with first- and second-generation agents; however, no consistent class-wide effect exists across most pathways. The evidence base remains fragmented, often derived from agent- or context-specific studies in heterogeneous populations, with uncertainty surrounding optimal timing of intervention. By bridging mechanistic understanding with clinical outcomes, this review highlights the importance of standardized assessment of BB effects, the development of personalized treatment approaches, and the pursuit of future research to address ongoing translational gaps. Full article

To further investigate the role of PKCλ/ι in Schistosoma japonicum-induced hepatic fibrosis, we employed a CD4⁺ T-cell-specific PKCλ/ι conditional knockout (KOSJ) mouse model, with wild-type (WTSJ) mice used as controls. Transcriptomic profiling of hepatic mRNA was used to reveal the immune regulatory mechanisms underlying the role of PKCλ/ι in the hepatic fibrosis caused by S. japonicum infection. Flow cytometry, RT–qPCR and ELISA were used to analyze the effects of PKCλ/ι on Tfh and Tfr cells, and single-cell RNA sequencing was used to elucidate the interactions between Tfr and B cells. The results showed that PKCλ/ι deficiency led to altered BCR signaling gene expression, reduced germinal center activity, and decreased anti-SEA antibody levels. Tfh cells and key factors including IL-21, CXCR5, and ICOS were downregulated, while Tfr cells and IL-10⁺ B cells increased. Additionally, hepatic neutrophils decreased and Treg/Tfr ratios rose, with enhanced IL-10-mediated cellular crosstalk. These findings indicate that PKCλ/ι deficiency attenuates liver fibrosis by inhibiting Tfh differentiation, promoting Tfr function, and activating IL-10-producing Breg cells, suggesting its potential as a therapeutic target. Full article

Cardiovascular diseases (CVDs) are increasingly being defined not only in terms of metabolic or purely vascular disorders, but also as complex immunometabolic disorders. One of the most groundbreaking discoveries in recent years is the role of neutrophil extracellular networks (NETs/NENs) as a key link between chronic vascular wall inflammation and thrombotic processes. In this article, we present a synthetic overview of the latest data on the biology of NETs/NENs and their impact on the development of atherosclerosis, endothelial dysfunction, and the mechanisms of immunothrombosis. We highlight how these structures contribute to the weakening of atherosclerotic plaque stability, impaired endothelial barrier integrity, platelet activation, and the initiation of the coagulation cascade. We also discuss the modulating role of classic risk factors such as hypertension, dyslipidemia, and exposure to tobacco smoke, which may increase the formation or hinder the elimination of NETs/NENs. We also focus on the practical application of this knowledge: we present biomarkers associated with the presence of NETs/NENs (cfDNA, MPO–DNA complexes, CitH3, NE), which may be useful in diagnostics and risk stratification, and we discuss innovative therapeutic strategies. In addition to classic methods for indirectly inhibiting NET/NEN formation (antiplatelet, anti-inflammatory, and immunometabolic agents), we present experimental approaches aimed at their neutralization and removal (e.g., DNase I, elastase, and myeloperoxidase inhibitors). We pay particular attention to the context of cardiac and cardiac surgical procedures (Percutaneous Coronary Intervention-PCI, coronary artery bypass grafting-CABG), where rapid NET/NEN bursts can increase the risk of acute thrombotic complications. The overall evidence indicates that NETs/NENs represent an innovative and promising research and therapeutic target, allowing us to view cardiovascular diseases in a new light—as a dynamic interaction of inflammatory, atherosclerotic, and thrombotic processes. This opens up new possibilities in diagnostics, combination treatment and personalisation of therapy, although further research and standardization of detection methods remain necessary. Full article

Endothelial dysfunction is an early driver of atherosclerosis, yet the direct impact of endogenous crystals such as cholesterol crystals and monosodium urate on endothelial activation remains incompletely understood. In this study, we examine how crystalline stimuli modulate human umbilical vein endothelial cells by assessing inflammatory signaling, mitochondrial respiration, and neutrophil recruitment. Using dose- and time-controlled experiments, we show that CC and MSU are internalized by endothelial cells, activating NF-κB and STAT3 signaling pathways and inducing a robust pro-inflammatory cytokine profile. Notably, CC caused marked mitochondrial dysfunction, evidenced by impaired respiratory capacity and loss of membrane potential, revealing a novel bioenergetic vulnerability in endothelial cells. Both direct crystal stimulation and exposure to crystal-primed conditioned media triggered endothelial adhesion molecule expression and promoted neutrophil adhesion, indicating that soluble mediators released upon crystal stimulation can propagate vascular inflammation. These findings demonstrate that crystalline stimuli are potent vascular danger signals capable of driving endothelial inflammation, mitochondrial impairment, and immune cell engagement, which are hallmarks of early atherogenesis. By elucidating these multifaceted endothelial responses, this study provides important mechanistic insights into how crystal-induced signals may contribute to vascular dysfunction and the early stages of atherogenesis. Full article

Colchicine, a natural alkaloid, has emerged as a promising anti-inflammatory therapy with applications in cardiovascular diseases, dermatological conditions, and COVID-19 management. Its mechanisms, including the modulation of neutrophil activity, the inhibition of the NLRP3 inflammasome, and the mitigation of cytokine storms, have expanded its therapeutic potential beyond traditional uses. This review synthesizes current evidence on colchicine’s clinical applications and mechanisms of action. In cardiovascular medicine, colchicine has been shown to reduce risks of pericarditis, coronary artery disease and atrial fibrillation. In dermatology, most evidence derives from small-scale studies, case series, and retrospective analyses, suggesting potential benefits in conditions such as leukocytoclastic vasculitis, cutaneous amyloidosis, and pemphigus, although these findings require confirmation through randomized controlled trials (RCTs). Emerging studies also indicate a potential role for colchicine in improving outcomes in severe COVID-19. Overall, colchicine demonstrates broad therapeutic utility, warranting further research to clarify its effectiveness across diverse clinical settings. Full article

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar–capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg/kg) and in vitro (0.1–1 mg/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1β), and signaling proteins (HIF-1α, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1α, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p < 0.01), collagen deposition by ~50%, and ROS accumulation by >60% relative to LPS (n = 6). The pro-inflammatory cytokines IL-6 and IL-1β were reduced by 55–70% at the protein level (p < 0.01). Harpagide dose-dependently suppressed HIF-1α and p-AKT expression while enhancing Nrf2 and HO-1 levels (p < 0.05). SPR confirmed direct binding of Harpagide to HIF-1α (KD = 8.73 µM), and the CETSA demonstrated enhanced thermal stability of HIF-1α. MD simulations revealed a stable binding conformation within the inhibitory/C-TAD region after 50 ns. Conclusions: This study reveals convergent immune–microenvironmental regulatory mechanisms across cellular and tissue levels in ALI and demonstrates the protective effects of Harpagide through multi-pathway modulation. These findings offer new insights into the pathogenesis of ALI and support the development of “one-drug, multilayer co-regulation” strategies for systemic inflammatory diseases. Full article

Immune cells like neutrophils, monocytes/macrophages, and lymphocytes play key roles in the development, progression, and resolution of deep vein thrombosis (DVT) by contributing to inflammation, coagulation, and fibrinolysis. IFN-γ, a cytokine mainly secreted by natural killer (NK) and T cells, is a critical factor in DVT pathogenesis. It links immune responses to coagulation activation by promoting endothelial activation, leukocyte recruitment, cytokine release, and coagulation imbalance. Its strong pro-inflammatory and prothrombotic effects make IFN-γ a promising target for DVT treatment beyond standard anticoagulants. Exploring ways to block IFN-γ signaling or its downstream effects could open doors to novel therapies for DVT, aiding in resolution and preventing post-thrombotic complications. This review delves into DVT pathophysiology, diagnostics, and management, emphasizing the importance of targeting immune cells and IFN-γ to advance treatment options. Full article

Legionella pneumophila (L. pneumophila) infection is characterized by a wide spectrum of manifestations, from influenza-like illness to life-threatening atypical pneumonia with multiorgan failure. The aim of our study was the assessment of in vitro and ex vivo neutrophil activation in L. pneumophila infections, as well as the role of neutrophils’ peptides such as LL-37 in infection. The ability of neutrophils to form ex vivo extracellular traps (NETs) in response to bacterial infection was examined by immunofluorescence. In parallel, patients’ sera, as well as opsonized standard L. pneumophila strains, were used for in vitro activation of neutrophils from healthy individuals. The serum levels of interleukins were assessed using the LEGENDplexTM Multi-Analyte Flow Assay Kit. Furthermore, citrullinated cf-DNA as a marker of neutrophil extracellular traps (NETs) was detected in the serum of patients with acute infection. It was demonstrated that neutrophils released NETs in vitro and ex vivo upon L. pneumophila (interaction in an autophagy-independent manner. Notably, IL-1b was detected on NETs, but an antimicrobial peptide LL-37 was absent. The lack of antimicrobial activity failed to inhibit bacterial proliferation. In addition, in vitro and ex vivo NETs formation was observed during the Clarithromycin treatment. Those NETs were decorated with bioactive antimicrobial peptide LL-37, which inhibits bacterial proliferation. The findings provide evidence that neutrophils release NETs in vitro and ex vivo by expressing the IL1β protein in them. The lack of expression of the antimicrobial peptide LL-37 on the NETs demonstrates the inability of the cells to inhibit proliferation, and consequently the elimination of L. pneumophila. Clarithromycin plays a dual role in the elimination. Full article

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients. Full article

This report describes a case of feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) in a 6-year-old spayed female European Shorthair cat presenting with chronic vomiting and weight loss. Endoscopic examination revealed a submucosal duodenal mass, and histopathological evaluation of endoscopic biopsies confirmed a diagnosis of FGESF. The cat was treated exclusively with oral prednisolone (1 mg/kg SID), leading to complete clinical remission within 15 days. Follow-up ultrasonography and endoscopy performed 30 days later confirmed full resolution of the mass, which was replaced by a focal mucosal depression. Histopathology at that site revealed chronic-active lymphoplasmacytic and neutrophilic enteritis with mild fibroplasia. A mild recurrence of duodenal thickening was observed after steroid tapering, which resolved upon dosage adjustment. The patient has remained clinically stable for 15 months with normal imaging and blood parameters. Full article

Gout is a form of sterile inflammatory arthritis in which monosodium urate (MSU) crystals deposit and provoke a neutrophil-predominant response, primarily driven by activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Here, we show that auranofin, a Food and Drug Administration (FDA)-approved anti-rheumatic agent, exerts anti-inflammatory effects in both in vitro and in vivo models of gout. Auranofin inhibited NLRP3 inflammasome activation in human THP-1 cells and murine macrophages, leading to reduced cleavage of caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18). In MSU crystal-induced mouse models, auranofin treatment reduced paw swelling, serum cytokine levels, and tissue inflammation. Notably, auranofin suppressed neutrophil migration and decreased expression of C-X-C motif chemokine ligand 1 (CXCL1) in inflamed foot tissue and air-pouch exudates. Mechanistically, auranofin disrupted the interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis, a key signaling pathway promoting neutrophil recruitment. Overexpression of IL-33 abolished the anti-inflammatory effects of auranofin, highlighting the central role of IL-33 in gout pathogenesis. Together, our findings suggest that auranofin alleviates MSU-induced inflammation by concurrently inhibiting NLRP3 inflammasome activation and IL-33-mediated neutrophil recruitment, supporting its potential as a dual-action therapeutic candidate for gout. Full article

Clinical studies have linked glyphosate exposure to substantial morbidity, with acute kidney injury occurring in some cases. Although the toxic effects of glyphosate-based herbicides (GBHs) have been reported in several studies, their molecular impact on renal function remains poorly understood. Given the kidney’s critical role in excretion, it is particularly susceptible to damage from xenobiotic exposure. In this study, we aim to identify N-glycomics and proteomics change in the kidney following chronic GBH exposure, to better understand the mechanisms behind glyphosate-induced kidney damage. Kidney tissues from female and male rats were analyzed using liquid chromatography–tandem mass spectrometry. The results revealed notable changes in the N-glycan composition, particularly in the fucosylated and sialofucosylated N-glycan types. The proteomic analysis revealed the activation of immune signaling and inflammatory pathways, including neutrophil degranulation, integrin signaling, and MHC class I antigen presentation. Transcription regulators, such as IL-6, STAT3, and NFE2L2, were upregulated, indicating a coordinated inflammatory and oxidative stress response. Sex-specific differences were apparent, with female rats exhibiting more pronounced alterations in both the N-glycan and protein expression profiles, suggesting a higher susceptibility to GBH-induced nephrotoxicity. These findings provide new evidence that chronic GBH exposure may trigger immune activation, inflammation, and potentially carcinogenic processes in the kidney. Full article

Neutrophils are among the first cells to be recruited to the lungs during Chlamydia pneumoniae infection in mouse models; however, their regulatory functions are not yet fully understood. This study examined the mechanisms and significance of IL-10-producing neutrophils throughout C. pneumoniae pulmonary infection in C57BL/6 mice. Our findings revealed that infection with C. pneumoniae induces IL-10 secretion in bone marrow-derived neutrophils, depending on Toll-like receptor 2 (TLR2) activation. This process involves TLR2-dependent mitochondrial reactive oxygen species (ROS) production, which triggers the endoplasmic reticulum (ER) stress pathway, including IRE1α and subsequent Xbp1 splicing. Inhibition of this pathway or depletion of neutrophils (using the 1A8 monoclonal antibody) significantly reduces IL-10 levels in bronchoalveolar lavage fluid (BALF) in vivo. Conversely, the absence of IL-10-producing neutrophils, whether through depletion or TLR2 deficiency, leads to increased IL-12p70 and IFN-γ-positive NK cells, along with decreased regulatory T cells and M2-like macrophages. This results in a lower bacterial burden in the lungs but causes more severe pulmonary damage and decreased survival rates. These findings highlight that IL-10 produced by neutrophils via the TLR2-mitochondrial ROS–ER stress pathway is essential for modulating pulmonary immune responses and maintaining immune homeostasis during C. pneumoniae infection, thereby preventing excessive inflammation and tissue damage. Full article

Sugarcane wax-derived policosanol (POL) is well recognized for its multifaceted biological activities, particularly in dyslipidemia management, whereas sugar cane extract powder (SEP), prepared from whole sugar juice blended with supplementary components, has not been thoroughly investigated for its biological activities and potential toxicities. Herein, the comparative dietary effect of four distinct SEPs (SEP-1 to SEP-4) and Cuban sugarcane wax extracted POL were examined to prevent the pathological events in high-cholesterol diet (HCD)-induced hyperlipidemic zebrafish. Among the SEPs, a 14-week intake of SEP-2 emerged with the least zebrafish survival probability (0.75, log-rank: χ² = 14.1, p = 0.015), while the POL supplemented group showed the utmost survival probability. A significant change in body weight and morphometric parameters was observed in the SEP-2 supplemented group compared to the HCD group, while non-significant changes had appeared in POL, SEP-1, SEP-3, and SEP-4 supplemented groups. The HCD elevated total cholesterol (TC) and triglyceride (TG) levels were significantly minimized by the supplementation of POL, SEP-1, and SEP-2. However, an augmented HDL-C level was only noticed in POL-supplemented zebrafish. Likewise, only the POL-supplemented group showed a reduction in blood glucose, malondialdehyde (MDA), AST, and ALT levels, and an elevation in sulfhydryl content, paraoxonase (PON), and ferric ion reduction (FRA) activity. Also, plasma from the POL-supplemented group showed the highest antioxidant activity and protected zebrafish embryos from carboxymethyllysine (CML)-induced toxicity and developmental deformities. POL effectively mitigated HCD-triggered hepatic neutrophil infiltration, steatosis, and the production of interleukin (IL)-6 and inhibited cellular senescence in the kidney and minimized the ROS generation and apoptosis in the brain. Additionally, POL substantially elevated spermatozoa count in the testis and safeguarded ovaries from HCD-generated ROS and senescence. The SEP products (SEP-1, SEP-3, and SEP-4) showed almost non-significant protective effect; however, SEP-2 exhibited an additive effect on the adversity posed by HCD in various organs and biochemical parameters. The multivariate examination, employing principal component analysis (PCA) and hierarchical cluster analysis (HCA), demonstrates the positive impact of POL on the HCD-induced pathological events in zebrafish, which are notably diverse, with the effect mediated by SEPs. The comparative study concludes that POL has a functional superiority over SEPs in mitigating adverse events in hyperlipidemic zebrafish. Full article