UBC9 is a key enzyme involved in SUMOylation, a post-translational modification that targets protein function, stability, transcriptional regulation, and localization to affect biological processes in host cells. Pathogens often target UBC9 by exploiting the host's SUMO system to modify their proteins with altered functionality, which in turn favors the pathogens' survival or invasion. Herein, we investigated the critical role of UBC9 in regulating the inflammatory response and susceptibility to Mycobacterium marinum (Mm) infection in zebrafish. We effectively knocked down the UBC9 expression using morpholino antisense oligonucleotides, which showed significant developmental abnormalities in zebrafish, particularly in cartilage formation. Our results indicated that UBC9 is essential for immune cell migration, as its knockdown led to impaired macrophage and neutrophil responses during inflammation. Furthermore, we investigated the impact of UBC9 on the zebrafish response to Mm, a close relative of the tuberculosis-causing bacterium. Our results showed that UBC9-knocked-down zebrafish displayed a slight increase in bacterial proliferation, suggesting a potential role of UBC9 in host's ability to control pathogen replication and spread. The study explores the complex interplay between UBC9 and the immune system and provides insights into the important role of UBC9 in immune regulation and pathogen defence.

Chronic kidney disease (CKD) is closely linked to chronic inflammation, which plays a key role in its progression. The study aimed to investigate the association between the aggregate index of systemic inflammation (AISI) and CKD prevalence. We analyzed data from the National Health and Nutrition Examination Survey, which was conducted between 2007 and 2018. Multivariate logistic regression analyses were used to assess the independent relationship between AISI and CKD. Nonlinear relationships between AISI and CKD were examined through smooth curve fitting and threshold effect analyses. A total of 24,386 adult participants were included. After controlling for possible confounding variables, a significant positive association between AISI and CKD was identified (OR = 1.05, [95% CI: 1.03-1.07], P < .001). Subgroup analyses and interaction tests revealed significant differences in this association across diabetes strata (P < .05). Smoothing curve analysis demonstrated a nonlinear positive correlation between AISI and CKD. Moreover, threshold analysis revealed a saturation effect with an inflection point at 720 (1000 cells/μL). Below this threshold (AISI < 720, 1000 cells/μL), AISI was significantly positively associated with CKD, while no significant association was observed above the threshold (AISI > 720, 1000 cells/μL). These findings reveal a notable positive correlation between AISI and CKD among adults in the United States, with an inflection point at 720 (1000 cells/μL). The AISI shows potential as an indicator associated with CKD, but further comprehensive prospective studies are needed to confirm its role in CKD development and its utility in clinical practice.

The era of relying on antibiotics for curing bacterial infections is rapidly approaching an end, necessitating development of non-antibiotic-based infection-control strategies. Dispersal of infectious biofilms is a potential strategy but yields dispersed bacteria in blood that may cause sepsis. We report a bromide-loaded, core-shell ZnO2-nanoparticle/Ce-based metal-organic framework (ZnO2@CeMOF/Br) of which the ZnO2 core degrades at pH ≤ 6.5, leaving the MOF's Ce node intact. ZnO2-core degradation initially generates a nonradical, relatively stable, low-oxidative hydrogen peroxide that can cleave matrix DNA causing dispersal of Staphylococcus aureus biofilms and reacts with bromide ions to form transient hypobromous acid. Hypobromous acid modulates macrophage polarization toward an M1-like phenotype to clear dispersed bacteria from blood. Subsequently the Ce3+/Ce4+ redox couple forming the Ce node acts as an electron shuttle upon oxidation/reduction to faciltate two catalytic reactions, maintaining hydrolysis of phosphodiester bonds and associated cleavage of matrix DNA as well as modulation of macrophage polarization. Neither growth of tissue cells or macrophages nor hemolysis are negatively affected by exposure to ZnO2@CeMOF/Br nanocatalysts at a ZnO2 nanoparticle over CeMOFs weight ratio ≤ 1.2, up until CeMOF concentrations less than at least 180 μg/mL. Under biosafe, low-turnover catalytic conditions, irrigation of infected wounds in diabetic mice with ZnO2@CeMOF/Br nanocatalysts (90 μg/mL) results in 100% survival, fast recovery of healthy body temperature and weight, lower numbers of CFUs in blood and wound and organ tissues, and macrophage polarization toward an M1-like phenotype, demonstrating potential of ZnO2@CeMOF/Br nanocatalysts for non-antibiotic-based infection control.

Despite the increasing awareness of the health risks associated with radiation exposure such as radiotherapy and accidents, effective treatments remain limited except for bone marrow damage. Radiation-induced skin damage is a critical concern as it is often accompanied by severe inflammation and delayed wound healing. Endothelial cells have emerged as a promising therapeutic target for addressing such radiation-induced damage. Neutrophils, as key mediators of the early inflammatory response, play a pivotal role in this process. The formation of neutrophil extracellular trap (NET) is particularly noteworthy, as it may directly contribute to exacerbating vascular damage. However, studies specifically exploring the role of NETs in radiation-induced skin injury and their impact on endothelial barrier function are limited. Therefore, this study aimed to evaluate the use of AZD9668, an orally administered NE inhibitor, as a therapeutic agent to mitigate NET-induced endothelial and skin damage. Irradiated skin showed increased neutrophil infiltration, NET formation, and vascular permeability in the mouse model. Neutrophil elastase (NE) inhibitor, AZD9668, decreased NET formation and NET-derived NE activity. And AZD9668 treatment restored endothelial dysfunction and regulated antioxidative factors in NET-treated irradiated HUVECs. In mouse model of radiation-induced skin injury, oral administration of AZD9668 improved endothelial tight junction expression, vascular leakage, and inflammatory reaction. Therefore, skin wound healing accelerated in the AZD9668-treated group. This study highlights the critical role of NET in radiation-induced skin damage and endothelial barrier disruption, addressing a previously underexplored area. AZD9668 effectively mitigated radiation-induced damage by preventing NET formation, preserving tight junction integrity, and reducing inflammation. These findings underscore the therapeutic potential of NET and NET-derived NE in the management of radiation-induced vascular and skin injuries.

Female reproductive tract infections (RTIs) are a major health challenge worldwide and are the leading cause of infertility and adverse pregnancy outcomes. The rising incidence of RTIs highlights their status as a major public health issue. Microbial dysbiosis, particularly bacterial, fungal, and viral infections, constitutes the primary etiological factor disrupting female reproductive health. Antimicrobial peptides (AMPs) are evolutionarily conserved host defense molecules that exhibit broad-spectrum antimicrobial activity against pathogens, as well as anti-inflammatory and immunomodulatory properties. This review systematically summarizes the structural diversity, biological sources, and mechanistic pathways of human-derived AMPs in combating RTIs, with a particular emphasis on their therapeutic potential in fertility preservation. Emerging evidence suggests AMPs as promising alternatives to conventional antibiotics in the post-antibiotic era.

The parasite of the genus Leishmania is the causative agent of diseases that affect humans called leishmaniasis. These diseases affect millions of people worldwide and the currently existing drugs are either very toxic or the parasites acquire resistance. Therefore, new elimination mechanisms need to be elucidated so that new therapeutic strategies can be developed. Much has already been discussed about the role of neutrophils in Leishmania infection, and their participation is still controversial. A recent study showed that receptors present in the neutrophil membrane, the purinergic receptors, can control the infection when activated, but the triggering mechanism has not been elucidated. In this review, we will address the possible participation of purinergic receptors expressed in the neutrophil extracellular membrane that may be participating in the detection of Leishmania infection and their possible effects during parasitism.

Neutrophil dysregulation is implicated in a spectrum of inflammatory pathologies, suggesting the potential for targeting neutrophilic hyperactivation as a pharmacological strategy to manage inflammatory disorders. Building upon prior research where 2-thiolphenoxychromone derivatives were found to inhibit neutrophilic generation of superoxide anions, this study focused on exploring the structure-activity relationship (SAR) of different C2 bridging moieties and anti-inflammatory effects using bioisosteric replacements and scaffold-hopping approaches. Among various chemotypes, the N-(4-oxo-4H-chromen-2-yl)benzenesulfonamide derivatives emerged as robust inhibitors of both superoxide anion generation and elastase release from fMLF-activated human neutrophils, with IC50 values in the single-digit micromolar range. Leveraging a forward pharmacology approach through computational prediction, compound 15b, a representative within this active molecular class, was discovered to exert these anti-inflammatory functions by blocking the p38α mitogen-activated protein kinase (MAPK) signaling cascade. This responded to a significant reduction in p38α MAPK and its downstream MK2 phosphorylation in activated neutrophils treated with 15b, with no apparent impact on extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) phosphorylation levels. Additionally, this molecule exhibited inhibitory potential on intracellular reactive oxygen species (ROS) production, granule exocytosis, and chemotactic responses. Collectively, this study provides a novel skeleton for the development of inhibitors targeting the p38α MAPK pathway to mitigate neutrophilic inflammation.

Nucleases are critical metabolic enzymes expressed by mycoplasmas to acquire nucleic acid precursors from the host for their parasitic existence. Certain nucleases, either membrane-bound or secreted, not only contribute to the growth of mycoplasmas but also serve as key virulence factors due to their unique spatial structures and physiological activity. The pathogenesis includes, but is not limited to, degradation of host DNA and RNA, leading to disruptions of nucleic acid metabolism and the induction of host cell apoptosis; degradation of neutrophil extracellular traps (NETs), allowing escape from neutrophil-mediated killing; and upregulation of inflammatory molecules to modulate the immune response of the host. Understanding the biological functions of nucleases is essential for gaining deeper insights into the virulence and immune evasion strategies of mycoplasmas, which can inform the development of novel approaches for the prevention, diagnosis, and treatment of mycoplasma infections.

Sepsis is a life-threatening condition characterized by widespread inflammatory response syndrome in the body resulting from infection. Previous studies have demonstrated that some inflammatory factors or nutritional elements contributed to deaths in patients diagnosed with sepsis. Nevertheless, the correlation between the (neutrophil + monocyte)/albumin (NMa) ratio and all-cause mortality of patients diagnosed with sepsis remains unclear. This study aims to investigate the association between the NMa ratio and all-cause mortality in sepsis patients and to develop a predictive model using machine learning techniques.

The clinical data were harvested from 13,851 patients with sepsis from the MIMIC-IV (3.1) database. We divided the subjects into four groups based on quartiles of the NMa ratio. The main endpoint was 30-day all-cause mortality, and the secondary endpoint was 90-day all-cause mortality. The relationship between the NMa ratio and adverse prognosis was investigated employing Cox proportional hazard regression, restricted cubic splines, and Kaplan‒Meier curves. Moreover, we employed Boruta algorithm to evaluate the predictive potential of the NMa ratio and established the prediction models utilizing machine learning algorithms.

After adjusting for confounders, each unit increase in the NMa ratio was associated with a 1.8% and 1.6% higher risk of 30-day and 90-day all-cause mortality, respectively (P < 0.001), indicating a linear relationship, and when treated as a categorical variable, the Quartile 4 group demonstrated a significantly higher mortality risk. Boruta feature selection also displayed that the NMa ratio possessed a higher Z score, and the models established utilizing the Cox and Random Forest algorithm identified excellent predictive performance (area under the curve (AUC) = 0.72, AUC = 0.74, respectively).

The NMa ratio is strongly and linearly associated with 30-day and 90-day all-cause mortality, with higher levels significantly increasing mortality risk, even after adjusting for potential confounders. Predictive models using Cox regression and Random Forest algorithms showed strong performance, indicating that the NMa ratio could function as a predictor of negative prognosis in patients with sepsis.

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.

The skin, the human body's largest organ, is perpetually exposed to environmental factors, rendering it vulnerable to potential injuries. Fascia, a vital connective tissue that is extensively distributed throughout the body, fulfils multiple functions, including support, compartmentalization, and force transmission. The role of fascia in skin wound healing has recently attracted considerable attention. In addition to providing mechanical support, fascia significantly contributes to intercellular signalling and tissue repair, establishing itself as a crucial participant in wound healing. This review synthesises the latest advancements in fascia research and its implications for skin wound healing.

New roles for immune cells, overcoming the classical cytotoxic response, have been highlighted by growing evidence. The immune cells, such as neutrophils, monocytes/macrophages, and eosinophils, are versatile cells involved in the release of web-like DNA structures called extracellular traps (ETs) which represent a relevant mechanism by which these cells prevent microbes' dissemination. In this process, many enzymes, such as elastase, myeloperoxidase (MPO), and microbicidal nuclear and granule proteins, which contribute to the clearance of entrapped microorganisms after DNA binding, are involved. However, an overproduction and release of ETs can cause unwanted and dangerous effects in the host, resulting in several pathological manifestations, among which are chronic inflammatory disorders, autoimmune diseases, cancer, and diabetes. In this review, we discuss the release mechanisms and the double-edged sword role of ETs both in physiological and in pathological contexts. In addition, we evaluated some possible strategies to target ETs aimed at either preventing their formation or degrading existing ones.

The production of soybean meal (SBM) can be linked to various issues related to the environment (e.g., deforestation, water waste, and transportation costs), and reducing its inclusion in pig diets by using alternative protein sources, such as insect meal, is an important challenge for nutritionists. This study aimed to compare the productive performance, dietary digestible energy (DE), nutrient digestibility, and some blood indices of growing Danube White pigs fed graded levels of Black Soldier fly (Hermetia illucens L.) larvae meal (BSFLM) at 0, 30, 60, 90, and 120 g/kg of diets, in replacement of SBM for 38 days, from 119 to 157 d old. Each diet was fed to eight pigs in individual boxes following randomization. Pigs grew according to breeders' recommendations and did not have any clinical health problems. Replacing SBM did not change (p > 0.05) the pigs' growth performance and DE, as only dietary fat digestibility increased in a linear fashion (p < 0.001), possibly due to the high BSFLM, i.e., the high-fat inclusion rate. There was a simultaneous rise in some oxidative damage indicators and an increase in antioxidant status, thus suggesting that further research involving longer feeding periods is needed to identify a potential time sequence of events. Overall, BSFLM is a promising ingredient in pig nutrition.

Neutrophils play an important role in regulating immune and inflammatory responses in patients with rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation and whether a neutrophil activation score could predict treatment response.

Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using enzyme-linked immunosorbent assay in plasma from patients with RA (n = 271) and healthy controls (n = 39). For patients with RA, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after receiving placebo and 2 and 4 mg baricitinib. Whole-blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil-related transcripts (n = 1,651).

Baseline levels of plasma neutrophil markers were elevated in patients with RA compared to healthy controls (P < 0.001). Receiving baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in patients with RA responding to treatment, as determined by American College of Rheumatology 20% improvement criteria. Whole-blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and Fcα receptor I upon reception of baricitinib in three randomized clinical trials involving patients with at various stages of disease-modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs (eg, a neutrophil activation score, at baseline, could predict treatment response to baricitinib). In contrast, C-reactive protein levels could not distinguish between responders and nonresponders.

Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine in treating patients with RA, not only based on symptoms but also based on immunophenotyping.

Behçet's disease (BD) and inflammatory bowel disease (IBD) are chronic inflammatory diseases characterized by immune system dysregulation. The critical role of neutrophils in these conditions is increasingly recognized. This study aimed to identify a shared set of neutrophils differentially expressed genes (NDEGs) to aid in the differential diagnosis of the two diseases.

Bioinformatics analysis of GEO data combined with WGCNA identified 65 key NDEGs. Functional enrichment and immune infiltration analyses were conducted. RT-qPCR validated six hub NDEGs in neutrophils from IBD and BD patients. Serum CD226 levels were measured by ELISA, and a ROC curve assessed its diagnostic value. Additionally, neutrophils were stimulated with patient serum, followed by Western blot analysis.

Immune infiltration analysis showed higher blood neutrophil levels in BD than in IBD. Neutrophil sequencing identified NDEGs upregulated in BD but downregulated in IBD, linked to T-cell receptor pathways. RT-PCR confirmed elevated FYN, CD99, SKAP1, and CD226 in BD neutrophils, while KLRG1 and MATK were higher in IBD. ELISA showed increased serum CD226 in BD. Western blot revealed higher Elastase and PAD4 in BD-stimulated neutrophils, while CXCL11 was elevated in IBD-stimulated neutrophils.

Our findings suggest that BD and IBD neutrophils may have distinct functional states, potentially linked to differential T-cell interactions. These insights highlight neutrophils' diverse roles in immune dysregulation and their potential as diagnostic markers and therapeutic targets.

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving activation of the immune system and the infiltration of immune cells. As the first immune cells to reach the site of inflammation, neutrophils perform their biological functions by releasing many active substances and forming neutrophil extracellular traps (NETs). The overactivated neutrophils in patients with RA not only directly damage tissues but also, more importantly, interact with various other immune cells and broadly activate innate and adaptive immunity, leading to irreversible joint damage. However, owing to the pivotal role and complex influence of neutrophils in maintaining homoeostasis, the treatment of RA by targeting neutrophils is very difficult. Therefore, a comprehensive understanding of the interaction pathways between neutrophils and various other immune cells is crucial for the development of neutrophils as a new therapeutic target for RA. In this study, the important role of neutrophils in the pathogenesis of RA through their crosstalk with various other immune cells and nonimmune cells is highlighted. The potential of epigenetic modification of neutrophils for exploring the pathogenesis of RA and developing therapeutic approaches is also discussed. In addition, several models for studying cell‒cell interactions are summarized to support further studies of neutrophils in the context of RA.

Neutrophils are the most abundant type of immune cells and also the most underestimated cell defenders in the human body. In fact, their lifespan has also been extensively revised in recent years, going from a half-life of 8-10 h to a longer lifespan of up to 5.4 days in humans; it has been discovered that their mechanisms of defense are multiple and finely modulated, and it has been suggested that the heterogeneity of neutrophils occurs as well as in other immune cells. Neutrophils also play a critical role in the wound healing process, and their involvement is not limited to the initial stages of defense against pathogens, but extends to the inflammatory phase of tissue reconstruction. Neutrophil heterogeneity has recently been reported at the presence of distinct subtypes expressing different functional states, which contribute uniquely to the different phases of innate immunity and wound healing. This heterogeneity can be induced by the local microenvironment, by the presence of specific cytokines and by the type of injury. The different functional states of neutrophils enable a finely tuned response to injury and stress, which is essential for effective healing. Understanding the functional heterogeneity of neutrophils in wound healing can unveil potential pathological profiles and therapeutic targets. Moreover, the understanding of neutrophil heterogeneity dynamics could help in designing strategies to manage excessive inflammation or impaired healing processes. This review highlights the complexity of neutrophil heterogeneity and its critical roles throughout the phases of wound healing.

Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic, and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome, and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of genes to survive conditions associated with transmission. Essential genes subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble antidesiccants. The candidate transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis.

Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis. Although immunosuppressive genes are upregulated in different immune cells, only neutrophils dramatically increase in the BALF of patients in immunosuppressive phase of sepsis. Five neutrophil subpopulations in BALF are identified, among which CXCR2+ and CD274 (PD-L1 coding gene)+IL1RN+ neutrophil subpopulations increased significantly during septic immunosuppression. Interestingly, a developmental trajectory from CXCR2+ to CD274+IL1RN+ neutrophil subpopulation is disclosed. Moreover, the therapeutic effect of CXCR2 blockade is observed on the survival of septic mice, along with a decreased number of PD-L1+ neutrophils. Taken together, the CXCR2+ neutrophil subpopulation is discovered as a contributor to immunosuppression in sepsis and identified it as a potential therapeutic target in sepsis treatment.

Pulmonary fibrosis, a chronic progressive lung disorder, can be the result of previous acute inflammation-associated lung injury and involves a wide variety of inflammatory cells, causing the deposition of extracellular matrix (ECM) components in the lungs. Such lung injury is often associated with excessive neutrophil function and the formation of DNA networks in the lungs, which are also some of the most important factors for fibrosis development. Acute lung injury with subsequent fibrosis was initiated in C57Bl/6 mice by a single intranasal (i.n.) administration of LPS. Starting from day 14, human recombinant DNase I in the form of Pulmozyme for topical administration was instilled i.n. twice a week at a dose of 50 U/mouse. Cell-free DNA (cfDNA), DNase activity, and cell content were analyzed in blood serum and bronchoalveolar lavage fluid (BALF). Inflammatory and fibrotic changes in lung tissue were evaluated by histological analysis. The gene expression profile in spleen-derived neutrophils was analyzed by RT-qPCR. We demonstrated that Pulmozyme significantly reduced connective tissue expansion in the lungs. However, despite the reliable antifibrotic effect, complete resolution of inflammation in the respiratory system of mice treated with Pulmozyme was not achieved, possibly due to enhanced granulocyte recruitment and changes in the nuclear/mitochondrial cfDNA balance in the BALF. Moreover, Pulmozyme introduction caused the enrichment of the spleen-derived neutrophil population by those with an unusual phenotype, combining pro-inflammatory and anti-inflammatory features, which can also maintain lung inflammation. Pulmozyme can be considered a promising drug for lung fibrosis management; however, the therapy may be accompanied by residual inflammation.

Recent studies suggest blood cells influence breast cancer, but no Mendelian randomization (MR) studies have confirmed a causal relationship between specific blood cell phenotypes and breast cancer. MR analysis of blood cell phenotypes used breast cancer data from Finngen R11, UKB, and open genome-wide association study databases. Meta-analyzed inverse variance weighted results were adjusted for multiple comparisons. The reverse relationship was also explored. MR and meta-analysis identified significant associations between specific blood cell phenotypes and breast cancer: neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation): odds ratio (OR) = 0.967, P = .0009; neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation): OR = 0.972, P = .031; white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation): OR = 0.972, P = .031; white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation): OR = 1.042, P = 8.15 × 10-5. And there was no reverse result. Neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation) and white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation) are protective factors for breast cancer. Conversely, neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation) and white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation) are risk factors for breast cancer.

This case report describes NETosis as a cause of thrombosis in an 18.3 kg, 8-year-old intact male mixed-breed dog with bacterial vasculitis. The dog presented with sudden paresis of the thoracic limb, characterized by cyanosis, absent arterial pulse, and decreased peripheral blood glucose levels. Doppler ultrasound confirmed thrombosis in the dorsal common digital artery. Histopathology post-amputation revealed bacterial vasculitis, thrombosis, and infarction, with immunohistochemical staining identifying extracellular citrullinated histone H3 (CitH3), indicative of NETs involvement. Treatment included antibiotics, pentoxifylline, and anticoagulants, showing transient improvement before disease progression and euthanasia due to respiratory signs. These findings suggest NETs as a potential therapeutic target for bacterial vasculitis in similar cases.

Platelet-rich plasma (PRP) is the platelet and leukocyte-containing plasmatic fraction of anticoagulated autologous blood. While evidence supporting the clinical use of PRP in dentistry is low, PRP is widely used in sports medicine, orthopedics, and dermatology. Its beneficial activity is commonly attributed to the growth factors released from platelets accumulating in PRP; however, evidence is indirect and not comprehensive. There is thus a demand to revisit PRP with respect to basic and translational science. This review is to (i) recapitulate protocols and tools to prepare PRP; (ii) to discuss the cellular and molecular composition of PRP with a focus on platelets, leukocytes, and the fibrin-rich extracellular matrix of coagulated plasma; and finally (iii) to discuss potential beneficial effects of PRP on a cellular and molecular level with an outlook on its current use in dentistry and other medical fields.

Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.

Immune-mediated inflammatory diseases (IMIDs) impose an immeasurable burden on individuals and society. While the conventional use of immunosuppressants and disease-modifying drugs has provided partial relief and control, their inevitable side effects and limited efficacy cast a shadow over finding a cure. Promising nucleic acid drugs have shown the potential to exert precise effects at the molecular level, with different classes of nucleic acids having regulatory functions through varying mechanisms. For the better delivery of nucleic acids, safe and effective viral vectors and non-viral delivery systems (including liposomes, polymers, etc.) have been intensively explored. Herein, after describing a range of nucleic acid categories and vectors, we focus on the application of therapeutic nucleic acid delivery in various IMIDs, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, asthma, ankylosing spondylitis, systemic lupus erythematosus, and uveitis. Molecules implicated in inflammation and immune dysregulation are abnormally expressed in a series of IMIDs, and their meticulous modulation through nucleic acid therapy results in varying degrees of remission and improvement of these diseases. By synthesizing findings centered on specific molecular targets, this review delivers a systematic elucidation and perspective towards advancing and utilization of nucleic acid therapeutics for managing IMIDs.

Inflammation is important in the development of systemic lupus erythematosus (SLE). Systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are novel clinical markers of inflammation with prognostic value in different diseases. However, the value of SIRI and SII as inflammation predictors in SLE remains unclear. This study explores the SIRI and SII as potential biomarkers for SLE.

Data from 280 individuals, including newly diagnosed SLE patients and healthy controls, were collected and divided into three groups: SLE without lupus nephritis (NLN) group (n=93), lupus nephritis (LN) group (n=96) and healthy control group (n=91). Differences in SIRI and SII among the three groups were compared. Logistic regression and Pearson linear analysis were used to analyze the predictive value and correlation of SIRI and SII with SLE and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). Receiver operating characteristic (ROC) curves evaluated SIRI and SII in predicting SLE, SLE disease activity, and LN.

The SIRI and SII values were significantly higher in the LN group compared to the NLN group (p<0.01). SII had the largest area under the ROC curve for predicting LN (AUC: 0.6775, 95%CI: 0.6020 - 0.7531). Logistic regression analysis showed SIRI and SII as independent risk factors for LN. Pearson linear analysis indicated SIRI and SII were positively correlated with SLEDAI-2K (rSIRI=0.25, rSII=0.24, p<0.05).

SIRI and SII are biomarkers of disease activity and renal involvement in SLE patients that can be used to evaluate and predict for SLE occurrence, disease activity, and lupus nephritis occurrence assessment.

Heliotropium indicum is well-known for its diverse medicinal properties, traditionally utilized to treat ailments such as diabetes, obesity, bacterial infections, inflammation, and diarrhea. This study aims to explore the anti-inflammatory effects of the extract using in vitro methods and to assess its drug-likeness potential using docking, PASS and ADME. Fractionations of crude methanol extract (CME) were undertaken in n-hexane (NHF), chloroform (CHF), and ethyl acetate (EAF). GC-MS analysis was conducted using Agilent technologies. All fractions were evaluated for radical scavenging and anti-inflammatory properties in vitro. Molecular docking was performed with PyRx and Biovia Discovery Studio, followed by drug-likeness analysis using Swiss ADME. The ethyl acetate fraction (EAF) showed the highest DPPH scavenging activity (IC50: 4.3 μg/ml), followed by chloroform (CHF, IC50: 12.95 μg/ml) and n-hexane fractions (NHF, IC50: 17.6 μg/ml). Catechin had an IC50 of 3.5 μg/ml. EAF and CHF also exhibited the highest hydroxyl radical scavenging activity (51.69 μg/ml). EAF demonstrated significant anti-inflammatory activity, inhibiting heat-induced hemolysis (71.90%), hypotonicity-induced hemolysis (67.18%), and AAPH-induced hemolysis (72.52%) at 400 μg/ml. Six major phytoconstituents in EAF, identified by GC-MS, were docked with COX-2. ADME and drug-likeness evaluations using the Lipinski's "rule of five" confirmed all compounds had acceptable pharmacokinetic properties to fulfill the pharmaceutical formulations requirement. The study depicts the first and novel report of GC-MS compounds on in silico analysis. Both EAF and CHF exhibit significant anti-inflammatory activity, indicating their potential as a source for developing new therapeutic agents for treating inflammation.

Neutrophils are short-lived cells of the innate immune system and represent 50-70% of the circulating leucocytes. Their primary role is antimicrobial defence which they accomplish through rapid migration to sites of inflammation followed by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETosis). While previously considered terminally differentiated cells, they have been shown to have great adaptability and to play a role in conditions ranging from cancer to autoimmunity. This review focuses on their role in allergic disease. In particular: their role as potential amplifiers of type 1 hypersensitivity reactions leading to anaphylaxis; their involvement in alternative pathways of food and drug allergy; their role in allergic rhinitis and asthma and neutrophil dysfunction in atopic dermatitis. The use of potential biomarkers and therapeutic targets is also discussed with a view to guiding future research.

Treponema denticola, a bacterium that forms a "red complex" with Porphyromonas gingivalis and Tannerella forsythia, is associated with periodontitis, pulpitis, and other oral infections. The major surface protein (Msp) is a surface glycoprotein with a relatively well-established overall domain structure (N-terminal, central and C-terminal regions) and a controversial tertiary structure. As one of the key virulence factors of T. denticola, Msp is associated with adherence, immune response, and pore formation by the microorganism. It also mediates several pathological changes in histocytes, such as cytoskeleton disruption, neutrophil phagocytosis, and phosphoinositide balance interruption. In addition, the Msp of T. denticola is also an ortholog of the Treponema pallidum repeat (Tpr) proteins and Msp or Msp-like proteins that have been detected in other oral treponeme species. This review will discuss the structure, pathogenicity and homologs of Msp produced by T. denticola, illuminate the controversy regarding the structure and membrane topology of native Msp, explore the potential roles of Msp in the mechanism of T. denticola immune escape and provide an overview of the cytotoxicity and adherence ability of Msp. Further understanding of the structure and functions of Msp will offer new insights that will help promote further investigations of the pathogenic mechanisms of T. denticola and other treponemes, leading to more effective prophylactic or therapeutic treatments for relevant diseases.

Neutrophils, traditionally considered as non-specific components of the innate immune system, have garnered considerable research interest due to their dual roles in both promoting and inhibiting tumor progression. This paper seeks to clarify the specific mechanisms by which neutrophils play a bidirectional role in tumor immunity and the factors that influence these roles. By conducting a comprehensive analysis and synthesis of a vast array of relevant literature, it has become evident that neutrophils can influence tumor development and invasive migration through various mechanisms, thereby exerting their anti-tumor effects. Conversely, they can also facilitate tumorigenesis and proliferation, as well as affect the normal physiological functions of other immune cells, thus exerting pro-tumor effects. Moreover, neutrophils are influenced by tumor cells and their unique microenvironment, which in turn affects their heterogeneity and plasticity. Neutrophils interact with tumor cells to regulate various aspects of their life activities precisely. This paper also identifies unresolved issues in the research concerning the bidirectional role of neutrophils in tumorigenesis and tumor development, offering new opportunities and challenges for advancing our understanding. This, in turn, can aid in the proper application of these insights to clinical treatment strategies.

Osteoporosis induces severe oxidative stress and disrupts bone metabolism, complicating the treatment of bone defects. Current therapies often have side effects and require lengthy bone regeneration periods. Hydrogels, known for their flexible mechanical properties and degradability, are promising carriers for drugs and bioactive factors in bone tissue engineering. However, they lack the ability to regulate the local pathological environment of osteoporosis and expedite bone repair. Polyphenols, with antioxidative, anti-inflammatory, and bone metabolism-regulating properties, have emerged as a solution. Combining hydrogels and polyphenols, polyphenol-based hydrogels can regulate local bone metabolism and oxidative stress while providing mechanical support and tissue adhesion, promoting osteoporotic bone regeneration. This review first provides a brief overview of the types of polyphenols and the mechanisms of polyphenols in facilitating adhesion, antioxidant, anti-inflammatory, and bone metabolism modulation in modulating the pathological environment of osteoporosis. Next, this review examines recent advances in hydrogels for the treatment of osteoporotic bone defects, including their use in angiogenesis, oxidative stress modulation, drug delivery, and stem cell therapy. Finally, it highlights the latest research on polyphenol hydrogels in osteoporotic bone defect regeneration. Overall, this review aims to facilitate the clinical application of polyphenol hydrogels for the treatment of osteoporotic bone defects.

The formation of neutrophil extracellular traps (NETs) is known as an important part of the innate immune response. Still, some mechanisms regarding their formation and role during a disease are not completely understood yet. To visualize NETs by immunofluorescence microscopy, a chemical fixation is required. Therefore, this study focused on the effect of chemical fixatives on immunofluorescence staining of selected neutrophil and NET-markers, including myeloperoxidase (MPO), DNA/histone-1-complexes and citrullinated histone H3 (H3cit). Neutrophils isolated from fresh human blood were stimulated with phorbol-12-myristate 13-acetate (PMA) to induce NETs and fixed with paraformaldehyde (PFA, 4%), glutardialdehyde (GA, 5%) or methanol (MeOH, 100%) using different incubation times depending on the used fixative. We found that different fixation times with PFA had no effect on the staining intensity of MPO or DNA/histone-1-complex antibodies. For the staining of H3cit, fixation with PFA for 24 h decreased the signal intensity whereas 30 min fixation time had no effect. In contrast, glutardialdehyde induced a high amount of autofluorescence, and the fixation with 100% MeOH resulted in visible cellular damage. Therefore, we recommend 15-30 min PFA fixation for the respective stainings. Our results provide a solid basis for future experiments to study neutrophil activation and NET-formation.

Hepatic ischemia-reperfusion (I/R) injury is the primary cause of liver dysfunction and liver failure, commonly occurring in liver transplantation, hepatectomy, and hemorrhagic shock. Polo-like kinase 2 (PLK2), a pivotal regulator of centriole duplication, plays a crucial role in cell proliferation and injury repair. However, the function of PLK2 in hepatic I/R remains unclear.

The effect of PLK2 was investigated in the mouse hepatic I/R model and the hepatocyte hypoxia-reoxygenation (H/R) model. Liver injury was assessed by serum transaminase and hematoxylin and eosin staining. Cell apoptosis was analyzed using TUNEL analysis and immunoblotting. Inflammatory factors were evaluated by reverse transcription-quantitative polymerase chain reaction. Mice or cultured cells during the I/R or H/R were treated by overexpressing PLK2. ROS fluorescence staining was used to assess oxidative stress injury.

PLK2 was upregulated after hepatic I/R injury. Overexpressed PLK2 significantly improved liver enzyme levels and alleviated liver histological injury. Moreover, PLK2 decreased hepatocyte apoptosis and inhibited the expression of inflammatory factors in liver. Mechanistically, PLK2 increased the phosphorylation of GSK3β and enhanced expression of the antioxidant enzyme HO-1, leading to less ROS production. Inhibition of the HO-1 aggravated ROS generation and abolished the protective effect of PLK2.

Overall, these findings revealed that PLK2 enhanced HO-1 expression and reduced oxidative stress damage in hepatic I/R injury, and this protective effect related to GSK3β activity.

The mechanisms of Pythium insidiosum-antigen (PIA) immunotherapy activating a patient's immune system are unknown. We evaluated the interleukin-8 (IL-8) serum levels during P. insidiosum infection and after vaccination with PIA in vascular pythiosis cases. Furthermore, we studied the anti-P. insidiosum activity of neutrophils stimulated with various concentrations of PIA ex vivo in 3 strains of P. insidiosum isolated from vascular pythiosis patients. IL-8 serum levels were evaluated using the ELISA technique. We assessed the effect of PIA-stimulated neutrophils on the viability of zoospores using MTT assay, visualized neutrophil extracellular trap (NET) formation via microscopy, and measured the levels of double-stranded DNA (dsDNA) using PicoGreen dsDNA quantitation assay in 3 strains of P. insidiosum isolated from vascular pythiosis patients. Serum levels of IL-8 gradually lowered from the early to the end phases of vaccination with PIA among the surviving group of vascular pythiosis cases. Neutrophils stimulated with 0.01 µg/ml PIA reduced zoospore viability significantly compared to PIA-unstimulated neutrophils for strain 1 and strain 3 (p < .05). Neutrophils stimulated with 0.01, 0.1, 1, and 10 µg/ml PIA exhibited significantly lower zoospore viability than PIA-unstimulated neutrophils for strain 2 (p < .05). IL-8 can be used as a biomarker for monitoring vascular pythiosis cases treated with the PIA vaccine. Also, anti-P. insidiosum activity of PIA-stimulated neutrophils was probably due to the disruption of cellular activity in zoospores rather than the mechanisms based on the formation of NETs.