Atherosclerosis is a leading cause of global mortality, driven by complex interactions between genetic, metabolic, and environmental factors. Among these, hyperhomocysteinemia (HHcy) has emerged as a significant and modifiable risk factor, contributing to endothelial dysfunction, oxidative stress, and vascular inflammation. Despite increasing recognition of its role in atherogenesis, the precise mechanisms and clinical implications of HHcy remain incompletely understood, necessitating a comprehensive review to connect recent mechanistic insights with practical applications.

We analyzed the various mechanisms whereby HHcy accelerates the progression of atherosclerosis, and conducted a comprehensive review of publications in the fields of HHcy and atherosclerosis.

HHcy promotes atherosclerosis through several mechanisms, including inflammation, oxidative stress, epigenetic modification, and lipoprotein metabolism alteration. Moreover, this discussion extends to current strategies for the prevention and clinical management of HHcy-induced atherosclerosis.

This review consolidates and elucidates the latest advancements and insights into the role of HHcy in atherosclerosis. The comprehensive narrative connects fundamental research with clinical applications. Contemporary studies highlight the complex interplay between HHcy and atherosclerosis, establishing HHcy as not only a contributing risk factor but also an accelerator of various atherogenic processes.

Plant-derived extracellular vesicles have recently been extracted and recognized as promising bioactive molecules, owing to their distinctive biological properties and inherent therapeutic activities. In this study, we investigated the physicochemical characteristics, bioactive properties, and therapeutic potential of Perilla frutescens-derived exosome-like nanoparticles (PELNs). Transmission electron microscopy (TEM) revealed that PELNs exhibited a cup-shaped morphology, with a lipid bilayer and a size distribution ranging from 40 to 200 nm (mean: 68.4 ± 13.0 nm). The cargoes in PELNs were analyzed through multi-omics and small RNA sequencing. In vivo studies on zebrafish demonstrated that PELNs are non-toxic at experimental concentrations. A reduction in neutrophil migration to injured fins evidenced the anti-inflammatory properties of PELNs. Furthermore, a meta-analysis of transcriptomic data identified hundreds of differentially expressed genes (DEGs) across 12 samples of three experimental groups. These DEGs were annotated into three categories following gene ontology (GO) enrichment analysis. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these DEGs were involved in immune-related pathways, including complement and coagulation cascades, systemic lupus erythematosus, PPAR signaling pathways, and antigen processing and presentation. Twelve selected DEGs were validated by quantitative real-time PCR (qRT-PCR), with particular confirmation of the mpx and lcp1 genes via in situ hybridization. Furthermore, PELNs demonstrated antioxidative effects by mitigating reactive oxygen species (ROS) levels, as evidenced by measurements of four oxidative stress (OS) indicators (i.e., SOD, CAT, GSH, and MDA) in zebrafish larvae subjected to H2O2-induced OS. In summary, PELNs exhibit substantial anti-inflammatory and antioxidant properties, underscoring their potential as therapeutic agents for treating various inflammatory diseases.

Actin is an extraordinarily complex protein whose functions are essential to cell motility, division, contraction, signaling, transport, tissular structures, DNA repair, and many more cellular activities critical to life for both animals and plants. It is one of the most abundant and conserved proteins and it exists in either a soluble, globular (monomeric, G-actin) or an insoluble, self-assembled (polymerized or filamentous actin, F-actin) conformation as a key component of the cytoskeleton. In the early 1990's little, if anything, was known about the impact of reactive oxygen species (ROS) on the biology of actin except that ROS could disrupt the actin cytoskeleton. Instructively, G-actin is susceptible to alteration by ROS, and thus, purification of G-actin is typically performed in the presence of strong antioxidants (like dithiothreitol) to limit its oxidative degradation. In contrast, F-actin is a more stable conformation and thus actin can be kept relatively intact in purified preparations as filaments at low temperature for extended periods of time. Both G- and F-actin interact with a myriad of intracellular proteins and at least with a couple of extracellular proteins, and these interactions are essential to the many actin functions. This review will show how, over the past 30 years, our understanding of the role of ROS for actin biology has evolved from noxious denaturizing agents to remarkable regulators of the actin cytoskeleton in cells and consequent cellular functions.

The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO registration number: CRD42022364004). Literature search (PubMed, January 19, 2023) identified 49 articles, which were meta-analyzed using a random-effects model. The risk of bias was evaluated using SYRCLE's tool. The pooled effect considering all studies showed that neutrophil depletion induced a consistent pain reduction. Inflammatory, joint, neuropathic, and visceral pain showed significant pain alleviation by neutrophil depletion with medium-large effect sizes. However, muscle and postoperative pain were not significantly alleviated by neutrophil depletion. Further analysis showed a differential contribution of neutrophils to pain outcomes. Neutrophils had a higher impact on mechanical hyperalgesia, followed by nociceptive behaviors and mechanical allodynia, with a smaller contribution to thermal hyperalgesia. Interspecies (mice or rats) differences were not appreciated. Analyses regarding intervention unveiled a lower pain reduction for some commonly used methods for neutrophil depletion, such as injection of antineutrophil serum or an anti-Gr-1 antibody, than for other agents such as administration of an anti-Ly6G antibody, fucoidan, vinblastine, CXCR1/2 inhibitors, and etanercept. In conclusion, the contribution of neutrophils to pain depends on pain etiology (experimental model), pain outcome, and the neutrophil depletion strategy. Further research is needed to improve our understanding on the mechanisms of these differences.

This study aimed to explore the molecular characteristics of neutrophil extracellular traps (NETs) in chronic rhinosinusitis with nasal polyps (CRSwNP). Differentially expressed gene analysis, weighted gene co-expression network analysis, and machine learning algorithms identified three core NETs-associated genes: CXCR4, CYBB, and PTAFR, which were significantly upregulated in CRSwNP patients. The diagnostic performance of these genes was evaluated using receiver operating characteristic (ROC) curves, and their clinical relevance was validated using multicenter data. Immune infiltration analysis showed strong correlations between these genes and neutrophil and immune cell infiltration. Single-cell RNA sequencing demonstrated that these genes were predominantly expressed in myeloid and immune cells and exhibited dynamic changes during disease progression. These genes may contribute to CRSwNP pathogenesis through IL-17 signaling and metabolism-related pathways. This study identifies novel biomarkers and therapeutic targets for precise diagnosis and personalized treatment of CRSwNP.

The potential of nanoparticles as effective drug delivery tools for treating failing hearts in heart failure remains a challenge. Leveraging the rapid infiltration of neutrophils into infarcted hearts after myocardial infarction (MI), we developed a nanoparticle platform engineered with neutrophil membrane proteins for the targeted delivery of TAPI-1, a TACE/ADAM17 inhibitor, to the inflamed myocardium, aiming to treat cardiac dysfunction and remodelling in rats with MI.

Neutrophil-mimic liposomal nanoparticles (Neu-LNPs) were constructed by integrating synthesized liposomal nanoparticles with LPS-stimulated neutrophil membrane fragments and then loaded with TAPI-1. MI rats were treated with TAPI-1 delivered via Neu-LNPs for 4 weeks. Left ventricular function was assessed by echocardiography and cardiac fibrosis was evaluated post-treatment. The novel Neu-LNPs maintained typical nanoparticle features, but with increased biocompatibility. Neu-LNPs demonstrated improved targeting ability and cellular internalization, facilitated by LFA1/Mac1/ICAM-1 interaction. Neu-LNPs displayed higher accumulation and cellular uptake by macrophages and cardiomyocytes in infarcted hearts post-MI, with a sustained duration. Treatments with TAPI-1-Neu-LNPs demonstrated greater protection against myocardial injury and cardiac dysfunction in MI rats compared to untargeted TAPI-1, along with reduced cardiac collagen deposition and expression of fibrosis biomarkers as well as altered immune cell compositions within the hearts.

Targeted treatment with TACE/ADAM17 inhibitor delivered via biomimetic nanoparticles exhibited pronounced advantages in improving left ventricle function, mitigating cardiac remodelling, and reducing inflammatory responses within the infarcted hearts. This study underscores the effectiveness of Neu-LNPs as a drug delivery strategy to enhance therapeutic efficacy in clinical settings.

The liver is a central metabolic organ, but is also hosting a unique immune microenvironment to sustain homeostasis and proper defense measures against injury threats in healthy individuals. Liver macrophages, mostly represented by the tissue-resident Kupffer cells and bone marrow- or monocyte-derived macrophages, are intricately involved in various aspects of liver homeostasis and disease, including tissue injury, inflammation, fibrogenesis and repair mechanisms.

We review recent findings on defining the liver macrophage landscape and their functions in liver diseases with the aim of highlighting potential targets for therapeutic interventions. A comprehensive literature search in PubMed and Google Scholar was conducted to identify relevant literature up to date.

Liver macrophages orchestrate key homeostatic and pathogenic processes in the liver. Thus, targeting liver macrophages represents an attractive strategy for drug development, e.g. to ameliorate liver inflammation, steatohepatitis or fibrosis. However, translation from fundamental research to therapies remains challenging due to the versatile nature of the liver macrophage compartment. Recent and major technical advances such as single-cell and spatially-resolved omics approaches deepened our understanding of macrophage biology at a molecular level. Yet, further studies are needed to identify suitable, etiology- and stage-dependent strategies for the treatment of liver diseases.

Out-of-hospital cardiac arrest (OHCA) survivors have more than one-third mortality rate. Numerous inflammatory indicators are available, and it should be feasible to identify a fast and accurate way to aid medical decisions. This retrospective cohort study included 247 patients with OHCA, hospitalized between January 2015 and August 2024. The study was conducted in the intensive care unit of China Medical University Hospital, Taichung, Taiwan. A variety of inflammatory markers, including interleukin-6, neutrophil to high-density lipoprotein cholesterol ratio (NHR), and C-reactive protein, were screened at 24 h after OHCA. The primary endpoint was the 90-day all-cause mortality. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves of NHR were analyzed. Possible risk factors for all-cause mortality were estimated by Cox regression modeling. NHR and interleukin-6 were similarly predictive of all-cause mortality in inflammatory response, and both were superior to C-reactive protein at 24 h after OHCA (p < 0.001). The area under the ROC curve of NHR was 0.74 (95% confidence interval [CI]: 0.66-0.81, p < 0.001), sensitivity: 0.68, and specificity: 0.68, and NHR = 16.1. The 90-day all-cause mortality rate for NHR > 16.1 compared to those with NHR ≤ 16.1 was 0.51 and 0.21, respectively, according to Kaplan-Meier curves analysis. The hazard ratio for NHR > 16.1 was 2.54 (95% CI: 1.68-3.82, p < 0.001). An NHR > 16.1 at 24 h after OHCA is a potential inflammatory marker for predicting all-cause mortality.

Lipocalin 2 (LCN2) and the TWEAK/Fn14 signaling pathways are pivotal in psoriasis, influencing epidermal development, inflammatory cell chemotaxis, and inflammatory factor release. Despite their significant roles, the intricate relationship between LCN2 and TWEAK/Fn14 pathways remains unclear. Our study revealed the correlation between the expression of TWEAK, LCN2, and Fn14 in psoriatic lesions. We found that TWEAK is expressed by keratinocytes and macrophages, while LCN2 is expressed by keratinocytes and neutrophils. Surface plasmon resonance experiments demonstrated binding between LCN2 and Fn14, which was further validated by co-immunoprecipitation and cellular co-localization via immunofluorescence. In vitro, LCN2 promoted macrophage differentiation and TWEAK secretion, enhanced TWEAK and Fn14 expression in keratinocytes, and activated the MAPK signaling pathway. TWEAK upregulated LCN2 expression in neutrophils but not in keratinocytes. Bulk RNA-seq analysis revealed a synergistic effect of LCN2 and TWEAK in promoting inflammatory cytokine expression in keratinocytes, with enhanced MAPK pathway activation in the presence of M5 cytokines. Lcn2 knockout reduced Fn14 expression in skin lesions and serum TWEAK levels of imiquimod-induced murine psoriasis model, while Fn14 knockout attenuated the epidermal hyperplasia-promoting effects of TWEAK and LCN2. Overexpression of Fn14 in keratinocytes led to higher TWEAK expression upon LCN2 stimulation, suggesting a self-reinforcing loop among TWEAK, LCN2, and Fn14. We propose that LCN2 synergizes with TWEAK through Fn14 to drive psoriasis pathogenesis.

Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes - including those with antitumour activity - and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.

This study analyzes data from the 2009-2018 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between the Aggregate Index of Systemic Inflammation (AISI), also referred to as the pan-immune-inflammation value (PIV), and Type 2 Diabetes Mellitus (T2DM) among adults in the United States. Furthermore, it evaluates the mediating effect of obesity indicators on this association.

This study included 9,947 individuals from NHANES and applied appropriate weighting techniques. To examine the relationship between AISI and T2DM, we used various statistical models, including weighted multivariable logistic regression, smooth curve fitting, threshold effect analysis, subgroup analysis, trend tests, mediation analysis, and Shapley additive explanations (SHAP) models.

This research included a total of 9,947 participants, with 3,220 diagnosed with T2DM, while 6,727 remained undiagnosed. Weighted multiple logistic regression with all covariates adjusted indicated that with every one-unit increment in AISI/1000, there was an 88.3% likelihood of T2DM occurrence (OR: 1.883, 95% CI: 1.378-2.571). The stratified analysis identified significant differences in this association based on age, biological sex, level of education, poverty-income ratio (PIR), tobacco consumption status, and body mass index (BMI). Interaction tests revealed a positive association between AISI and T2DM, apart from PIR, BMI, age, education attainment, race, gender, tobacco use status, Estimated Glomerular Filtration Rate(eGFR), platelet count, and high blood pressure, with none of the interaction p-values falling below 0.05. Nevertheless, the occurrence of cardiovascular disease (CVD) among participants may affect the strength of this relationship, where an interaction p-value was less than 0.05. Additionally, smoothing curve fitting revealed a nonlinear relationship between AISI and T2DM, marking a significant change at AISI/1000 of 0.21. Mediation analysis indicated that five obesity-related indicators-LAP, VAI, WHtR, WWI and ABSI - partly mediated the association between AISI/1000 and T2DM.

An increase in AISI is associated with an elevated probability of T2DM, with obesity indicators potentially mediating this relationship. Reducing AISI and managing obesity may help prevent T2DM. However, with the cross-sectional design of this study, causal relationships cannot be established. Future research should utilize longitudinal studies to confirm these findings.

Studies indicate an association between biological aging and orthopedic diseases, but the causality remains unclear.

This study aims to investigate the bidirectional causal relationship between molecular markers of biological aging age and orthopedic conditions.

A two-sample Mendelian randomization (MR) analysis based on a genome-wide association study (GWAS) was conducted to explore these causal relationships. Analysis methods included inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. Sensitivity analyses involved Cochran's Q, MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests.

The forward MR analysis identified several causal relationships: granulocyte proportions influenced intervertebral disc degeneration (IVDD) (OR 0.2316, P = 0.0101) and low back pain (LBP) (OR 0.2624, P = 0.007); telomere length (TL) affected cervical spondylosis (C/S) (OR 0.8759, P = 0.0167) and IVDD (OR 0.9184, P = 0.023); fibroblast growth factor-23 (FGF-23) impacted frozen shoulder (FS) (OR 1.2424, P = 0.0316); and HannumAge influenced C/S (OR 0.9518, P = 0.0233). The reverse MR analysis found that FS influenced TL (OR 0.9582, P = 0.0002) and α-Klotho (OR 0.7592, P = 0.0256), while sciatica affected TL (OR 0.9344, P = 0.0055) and C/S impacted PhenoAge (OR 1.6583, P = 0.0131) after outlier exclusion. Cochran's Q indicated heterogeneity in certain analyses, and MR-Egger showed no horizontal pleiotropy in significant causal associations.

This study suggests a potential causal associations between molecular markers of biological aging and orthopedic diseases, suggesting avenues for future research into the underlying mechanisms.

Atherosclerosis, driven by inflammation, is a leading cause of cardiovascular events. Recent clinical trials have highlighted the therapeutic potential of anti-inflammatory treatments. Consequently, colchicine is being recommended for secondary prevention in current guidelines, although the drug's mechanistic actions are not fully understood.

To this end, we conducted a multiomic investigation of colchicine's effect on human carotid plaques. Sections from endarterectomy specimens were exposed to colchicine at concentrations of 2 ng/ml and 10 ng/ml ex vivo for 24 h and compared to untreated segments of the same plaque. Gene expression changes were analyzed by bulk RNA sequencing, and plaque secretomes underwent mass spectrometry for proteomic analysis. In situ cell proliferation was assessed by histology.

Our data indicate, that colchicine suppresses neutrophil and platelet degranulation and activation, collagen degradation and atheromatous plaque macrophage proliferation in a dose-dependent manner in human plaques, while stimulating myofibroblast activation. Unexpectedly, interleukine (IL)-1beta release from colchicine treated plaques was not reduced. These results indicate that the inflammasome may not be the predominant target of low-dose colchicine in human carotid artery plaques.

Our study identifies multifactorial pathways through which colchicine, the first cardiovascular guideline-recommended anti-inflammatory drug, predominantly acts on human atherosclerotic lesions beyond the inflammasome. Targeting neutrophil and platelet degranulation, collagen degradation and macrophage proliferation, selectively, may provide substantial therapeutic benefit in atherosclerotic cardiovascular disease without colchicine's undesired side effects.

Metabolic dysfunction - Associated Steatotic Liver Disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), poses a significant clinical burden due to its high prevalence and potential progression to fibrosis. While neutrophil extracellular traps (NETs) have been implicated in MASLD progression, their specific role in fibrosis remains unclear. This study integrates transcriptomic and single-cell data using weighted gene co-expression network analysis (WGCNA), causal WGCNA (CWGCNA), single-sample gene set enrichment analysis (ssGSEA), gene set variation analysis (GSVA), and linear models for microarray data (Limma) to identify key genes driving steatosis-to-fibrosis transition. Validation in human serum, mouse liver tissue, and mouse serum confirmed that SERPINE1 and THBS1 as robust non-invasive biomarkers with strong diagnostic performance. When combined with clinical features, these markers improved fibrosis prediction accuracy in MASLD patients. Additionally, SERPINE1 appears to mediate interactions between hepatic stellate cells and neutrophils, highlighting a novel therapeutic target. Overall, our findings reveal that NETs-related genes, particularly SERPINE1 and THBS1, hold strong diagnostic value for early-stage fibrosis in MASLD. Targeting SERPINE1 in hepatic stellate cells offers a promising strategy for therapeutic intervention. This study provides a novel framework for non-invasive MASLD fibrosis prediction and lays the foundation for targeted interventions to mitigate disease progression.

Blood cell phenotypes are routinely tested in healthcare to inform clinical decisions. Genetic variants influencing mean blood cell phenotypes have been used to understand disease aetiology and improve prediction; however, additional information may be captured by genetic effects on observed variance. Here, we mapped variance quantitative trait loci (vQTL), i.e. genetic loci associated with trait variance, for 29 blood cell phenotypes from the UK Biobank (N ~ 408,111). We discovered 176 independent blood cell vQTLs, of which 147 were not found by additive QTL mapping. vQTLs displayed on average 1.8-fold stronger negative selection than additive QTL, highlighting that selection acts to reduce extreme blood cell phenotypes. Variance polygenic scores (vPGSs) were constructed to stratify individuals in the INTERVAL cohort (N ~ 40,466), where the genetically most variable individuals had increased conventional PGS accuracy (by ~19%) relative to the genetically least variable individuals. Genetic prediction of blood cell traits improved by ~10% on average combining PGS with vPGS. Using Mendelian randomisation and vPGS association analyses, we found that alcohol consumption significantly increased blood cell trait variances highlighting the utility of blood cell vQTLs and vPGSs to provide novel insight into phenotype aetiology as well as improve prediction.

Bone is a dynamic tissue that constantly undergoes remodeling processes throughout life to maintain its structure and integrity. During this process, physiological bone turnover, which is shaped by apoptosis, occurs in cells in the bone microenvironment. The clearance of these apoptotic cells (ACs) is executed by phagocytes through a process called efferocytosis, which simply means taking to the grave "burial." Efferocytosis is a multistage process involving the recognition, binding, internalization, and digestion of ACs, culminating in the resolution of inflammation. Critically, aberrations in efferocytosis lead to the accumulation of apoptotic corpses, impairing tissue homeostasis and contributing to various pathologies as well as bone-related diseases. Emerging evidence suggests that modulating/activating efferocytosis at any stage represents a promising therapeutic strategy for managing bone-related diseases, especially those associated with aging and inflammation. This review discusses the current understanding of the cellular and molecular mechanisms of efferocytosis, its roles within the bone microenvironment, and potential therapeutic interventions targeting efferocytosis in age-related bone diseases.

Genome-wide association studies (GWAS) have identified thousands of disease-associated loci, yet their interpretation remains limited by the heterogeneity of underlying biological processes. We propose Joint Pleiotropic and Epigenomic Partitioning (J-PEP), a clustering framework that integrates pleiotropic SNP effects on auxiliary traits and tissue-specific epigenomic data to partition disease-associated loci into biologically distinct clusters. To benchmark J-PEP against existing methods, we introduce a metric-Pleiotropic and Epigenomic Prediction Accuracy (PEPA)-that evaluates how well the clusters predict SNP-to-trait and SNP-to-tissue associations using off-chromosome data, avoiding overfitting. Applying J-PEP to GWAS summary statistics for 165 diseases/traits (average N = 290 K ), we attained 16-30% higher PEPA than pleiotropic or epigenomic partitioning approaches with larger improvements for well-powered traits, consistent with simulations; these gains arise from J-PEP's tendency to upweight correlated structure-signals present in both auxiliary trait and tissue data-thereby emphasizing shared components. For type 2 diabetes (T2D), J-PEP identified clusters refining canonical pathological processes while revealing underexplored immune and developmental signals. For hypertension (HTN), J-PEP identified stromal and adrenal-endocrine processes that were not identified in prior analyses. For neutrophil count, J-PEP identified hematopoietic, hepatic-inflammatory, and neuroimmune processes, expanding biological interpretation beyond classical immune regulation. Notably, integrating single-cell chromatin accessibility data refined bulk-based clusters, enhancing cell-type resolution and specificity. For T2D, single-cell data refined a bulk endocrine cluster to pancreatic islet β -cells, consistent with established β -cell dysfunction in insulin deficiency; for HTN, single-cell data refined a bulk endocrine cluster to adrenal cortex cells, consistent with a GO enrichment for neutrophil-mediated inflammation that implicates feedback between aldosterone production in the adrenal gland and local immune signaling. In conclusion, J-PEP provides a principled framework for partitioning GWAS loci into interpretable, tissue-informed clusters that provide biological insights on complex disease.

Acute lung injury (ALI) is a common and life-threatening complication in patients with sepsis, with pro-inflammatory cell pyroptosis playing a crucial role in the associated organ damage. In this study, we aimed to identify potential therapeutic targets. Utilizing the GEO database (GSE232753), we analyzed the differentially expressed genes in the peripheral blood of healthy individuals and sepsis patients, identifying the significantly upregulated gene S100A8. Subsequently, we constructed a septic ALI model using lipopolysaccharide (LPS). Notably, S100A8 was highly expressed not only in serum and bronchoalveolar lavage fluid (BALF) but also in neutrophil exosomes. We then co-incubated BEAS-2B cells with neutrophil exosomes that were either treated or untreated with LPS. Cell proliferation activity was assessed using the CCK-8 assay, cell death was evaluated through propidium iodide (PI) staining, and the changes in pyroptosis indicators were detected via Western blot and ELISA. To further validate that LPS-induced neutrophil exosomes promote BEAS-2B cell pyroptosis through the delivery of S100A8, we conducted additional experiments involving the addition of S100A8 protein alone or S100A8 antibody in conjunction with neutrophil exosome treatment, followed by relevant assessments. Moreover, in vivo validation was also performed. Mechanistically, we revealed that S100A8 induces pyroptosis in BEAS-2B cells through the TLR4 signaling pathway. In conclusion, our findings provide new promising targets for the treatment of septic ALI.

The incidence and burden of skin wounds, especially chronic and complex wounds, have a profound impact on healthcare. Effective wound healing strategies require a multidisciplinary approach, and advances in materials science and bioengineering have paved the way for the development of novel wound healing dressing. In this context, electrospun nanofibers can mimic the architecture of the natural extracellular matrix and provide new opportunities for wound healing. Inspired by the bioelectric phenomena in the human body, electrospun nanofibrous scaffolds with electroactive characteristics are gaining widespread attention and gradually emerging. To this end, this review first summarizes the basic process of wound healing, the causes of chronic wounds, and the current status of clinical treatment, highlighting the urgency and importance of wound dressings. Then, the biological effects of electric fields, the preparation materials, and manufacturing techniques of electroactive electrospun nanofibrous (EEN) scaffolds are discussed. The latest progress of EEN scaffolds in enhancing skin wound healing is systematically reviewed, mainly including treatment and monitoring. Finally, the importance of EEN scaffold strategies to enhance wound healing is emphasized, and the challenges and prospects of EEN scaffolds are summarized.

Tissue repair represents a highly intricate and ordered dynamic process, critically reliant on the orchestration of immune cells. Among these, neutrophils, the most abundant leukocytes in the body, emerge as the initial immune responders at injury sites. Traditionally recognized for their antimicrobial functions in innate immunity, neutrophils now garner attention for their indispensable roles in tissue repair. This review delves into their novel functions during the early stages of tissue injury. We elucidate the mechanisms underlying neutrophil recruitment and activation following tissue damage and explore their contributions to vascular network formation. Furthermore, we investigate the pivotal role of neutrophils during the initial phase of repair across different tissue types. Of particular interest is the investigation into how the fate of neutrophils influences overall tissue healing outcomes. By shedding light on these emerging aspects of neutrophil function in tissue repair, this review aims to pave the way for novel strategies and approaches in future organ defect repair, regeneration studies, and advancements in tissue engineering. The insights provided here have the potential to significantly impact the field of tissue repair and regeneration.

Neutrophils play a key role in sepsis-associated acute kidney injury (SAKI), a common and life-threatening complication of organ failure. High mobility group box 1 (HMGB1) modulates inflammatory responses and the formation of neutrophil extracellular traps (NETs). The present work aimed to explore whether HMGB1 lactylation promotes NET formation and exacerbates SAKI.

Venous blood samples were collected from healthy volunteers and SAKI patients. A SAKI mouse model was established using the cecal ligation and puncture method. A coculture system of macrophage-derived exosomes and neutrophils was established. Macrophage-derived exosomes were isolated and identified. ELISAs, immunofluorescence staining, coimmunoprecipitation, and Western blotting were utilized to determine protein levels.

Elevated blood lactate levels were associated with increased HMGB1 levels in patients with SAKI. In mouse models, lactate increased HMGB1 expression, promoted NET formation, and exacerbated SAKI. Lactate stimulated M1 macrophages to secrete exosomes, leading to the accumulation and release of HMGB1 in the cytoplasm. Additionally, lactate promoted HMGB1 lactylation in macrophages, triggering the release of mitochondrial DNA from neutrophils and activating the cyclic GMP‒AMP synthase/stimulator of interferon genes pathway.

This study revealed that lactate-induced HMGB1 lactylation in macrophages plays a role in promoting NET formation in SAKI through the cGAS/STING pathway. These findings suggest that HMGB1 could be a potential target for therapeutic intervention in SAKI.

Despite advances in research, studies on predictive models for Non-Alcoholic Fatty Liver Disease (NAFLD)-related fibrosis remain limited. Identifying new biomarkers to distinguish Non-Alcoholic Steatohepatitis (NASH) from NAFLD would aid in the treatment of NASH. Gene expression and clinical profiles of NAFL and NASH patients were collected from databases. Differentially expressed genes with prognostic value were used to construct predictive model. Validation of fibrosis stage-related pyroptosis-related genes (PRGs) was performed using Sprague-Dawley rats liver fibrosis models induced by CCl4 or PS. Immune cell infiltration assessment demonstrated that stromal score, immune score, and ESTIMATE score were higher in patients with NASH compared to those with NAFL. BAX, BAK1, PYCARD, and NLRP3 were identified as hub genes that exhibit a strong correlation with fibrosis stage. Additionally, the expression of these genes was increased in fibrotic liver tissues induced by CCl4 and PS. The pyroptosis-associated gene signature effectively predicts the degree of liver fibrosis in NASH patients. Our study indicates that BAX, BAK1, PYCARD, and NLRP3 might serve as biomarkers for NASH-associated fibrosis.

Lung adenocarcinoma (LUAD) is a major subtype of lung cancer and one of the deadliest cancers in humans. Dysregulation of miRNA activity in tumor-associated neutrophils (TANs) in the tumor microenvironment plays an important role in the occurrence and development of LUAD.

In this study, the miReact algorithm was used to analyze the single-cell RNA sequencing data of LUAD samples to reveal the miRNA profile characteristics of TANs in LUAD patients. The function of miR-941 was investigated in vivo and in vitro. The target gene and underlying signaling pathway of miR-941 were predicted and validated with qPCR, luciferase assay, WB and ELISA assay.

The results indicated the crucial role of TANs, especially N2-TANs in LUAD and miR-941 activity was significantly upregulated in TANs of LUAD patients. MiR-941 overexpression promoted the proliferation, invasion, migration and anti-apoptosis of A549 and H1299. In vivo xenograft mouse model confirmed that miR-941 overexpression enhanced the growth of tumors formed by H1299 cells. Bioinformatics analysis showed that miR-941 targeted the tumor suppressor gene FOXN4, and we confirmed that FOXN4 overexpression could counteract the malignant effects of miR-941. In addition, miR-941 may drive LUAD progression through the FOXN4/TGF-β feedback signaling loop and participate in the N2-TAN polarization.

In summary, these findings reveal the key role of N2-TANs and the miR-941/FOXN4/TGF-β signaling loop in LUAD progression and provide potential therapeutic targets for future interventions.

Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD.

This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics.

PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001).

This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

Pediatric intensive care patients are particularly susceptible to severe bacterial infections because of ineffective neutrophil responses. The reasons why neutrophils of newborns are less responsive than those of adults are not clear. Because adenosine triphosphate and adenosine tightly regulate neutrophils, we studied whether the adenosine triphosphate and adenosine levels in the blood of newborn mice could impair the function of their neutrophils. We observed significant changes in plasma adenosine triphosphate and adenosine levels throughout the lifespan of mice. Adenosine levels in newborns were significantly higher than in older mice, while adenosine triphosphate levels were significantly lower. These changes were particularly striking in newborn and juvenile mice with adenosine triphosphate and adenosine levels of about 80 and 600 nM in newborns vs 130 and 190 nM in juveniles, respectively. The ratios of the adenosine triphosphate vs adenosine levels of newborns were (with 0.2) significantly lower than those of juveniles (1.4) and adults (0.5). These low adenosine triphosphate/adenosine ratios correlated with significantly weakened neutrophil activation responses following in vitro stimulation with a formyl peptide receptor agonist and a markedly higher morbidity and mortality rate of newborns following bacterial infection. We found that enhanced adenosine monophosphate hydrolysis via CD73, a lack of adenosine breakdown by adenosine deaminase, and reduced adenosine uptake by nucleoside transporters are responsible for the low adenosine triphosphate/adenosine ratios in blood of newborn mice. We conclude that the extracellular adenosine accumulation in newborn mice impairs inflammatory responses and reduces the ability of neutrophils to mount effective antimicrobial defenses against bacterial infections.

Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand. While lipolysis is essential for short term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves. Here, we report that β-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK activation in adipocytes. Recruited neutrophils locally secrete IL-1β, which suppresses lipolysis and limits excessive energy expenditure. Neutrophil depletion or blockade of IL-1β production increased lipolysis, leading to reduced WAT mass upon repeated β3-adrenergic stimulation. Together, these findings reveal an unexpected role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in maintaining energy homeostasis.

Gallstones are a common digestive disorder, with a global prevalence of 10%-15%, posing a significant economic burden on public health. The formation of gallstones is closely associated with inflammation and nutritional status. The Advanced Lung Cancer Inflammation Index (ALI) is a composite measure for assessing inflammation and nutritional status; however, its relationship with gallstone risk remains unclear. This study aims to investigate the association between ALI and gallstone prevalence among U.S. adults.

This study is based on data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and includes 5,826 adults aged 20 years and older. The Advanced Lung Cancer Inflammation Index (ALI) was calculated using body mass index (BMI), serum albumin levels, and the neutrophil-to-lymphocyte ratio (NLR). The prevalence of gallstones was determined through questionnaire surveys. Multivariable logistic regression models were employed to analyze the relationship between ALI and the risk of gallstones. Additionally, trend analysis, smooth curve fitting, and subgroup analyses were conducted.

The study results showed a significant positive correlation between ALI levels and the risk of gallstone disease. After fully adjusting for covariates, each unit increase in lnALI was associated with a 42% increase in the risk of gallstone disease (OR =  1.42, 95% CI: 1.12-1.80). Trend analysis indicated a significant dose-response relationship between ALI and gallstone risk (P for trend <  0.01). Subgroup analysis further revealed that the correlation between ALI and gallstone risk was more pronounced in females, non-diabetic patients, individuals with higher education levels, those with insufficient physical activity, and non-drinkers, with gender showing a significant interaction effect (interaction P <  0.05). Smooth curve fitting further validated the linear relationship between ALI and gallstone risk, and this association was particularly prominent in the female population.

This study demonstrates that ALI is significantly associated with the risk of gallstones, particularly among women. As a simple and readily accessible indicator, ALI may help identify high-risk populations and provide a new clinical tool for the prevention and management of gallstones. Future longitudinal studies should further validate these findings and evaluate the predictive value of ALI across different populations.

Sanhe cattle are domestically bred dual-purpose (i.e., milk and meat) cattle in northeast China that exhibit exceptional adaptability, resilience, and milk composition traits. Nevertheless, few studies that have analyzed the transcriptome of Sanhe cattle and elucidated the key pathways and genes accountable for its immune and production traits. Weighted gene co-expression network analysis is effective for cattle genetic studies. In this study, with Holstein cattle (n = 82) serving as the dairy breed, we aimed to investigate the manifestations and regulatory pathways of the health and milk composition traits for the Sanhe cattle population (n = 61). We employed principal composition analysis and pathway scoring to compare the distinct characteristics between the 2 cattle breeds using transcriptome, routine blood examination, milk composition, and dairy herd improvement data. We then identified 20 hub genes and potentially crucial pathways that were specifically and significantly correlated with the health and milk composition traits of Sanhe cattle by weighted co-expression network analysis and enrichment analysis. We discovered 56 hub genes that might give rise to commonalities and differences in health and milk composition between Sanhe cattle and Holstein cattle. Finally, we examined the differences in hub gene expression in health and milk composition traits between Sanhe cattle and Holstein cattle using correlation analysis. Overall, this study establishes a foundation for further exploration of the molecular markers related to the health and milk composition traits of Sanhe cattle.

Neutrophils are key players in the innate immune system, responsible for rapid responses to infections through mechanisms such as phagocytosis and the release of reactive oxygen species (ROS). Beyond their role in host defense, neutrophils also contribute to the pathogenesis of various diseases, including infections, metabolic disorders, autoimmune diseases, and cancer. Understanding the immunosuppressive role of neutrophils, particularly through markers like human neutrophil lipocalin (HNL) and the chemokine receptor CXCR3, is crucial for developing targeted therapeutic strategies.

This study involved 200 participants divided into four groups: 50 patients with acute respiratory infection, 50 COVID-19 recovered patients, 50 oncology patients, and 50 healthy donors as controls. Peripheral blood samples were collected and analyzed using enzyme-linked immunoassay (ELISA) to quantify levels of HNL and CXCR3. Data were analyzed using SPSS version 25.0, employing descriptive statistics, the Shapiro-Wilk test for normality, one-way ANOVA for normally distributed variables, and the Kruskal-Wallis test for non-normally distributed variables. Post-hoc comparisons were conducted using Tukey's HSD and Dunn's tests.

CXCR3 levels were stable across groups, with no significant differences found. Acute respiratory infection patients had an average CXCR3 level of 150 ± 20 pg/ml, while COVID-19 recovered patients had slightly lower levels at 140 ± 18 pg/ml. Oncology patients had elevated CXCR3 levels at 160 ± 22 pg/ml, similar to healthy donors at 150 ± 19 pg/ml. HNL levels varied more, with COVID-19 recovered patients showing notably lower levels (100 ± 12 ng/ml) compared to other groups. Oncology patients exhibited higher HNL levels, especially those with prostate cancer (150 ± 20 ng/ml).

The findings highlight the consistent expression of CXCR3 across various conditions, making it a reliable marker for immune response assessment. The distinct HNL profiles, particularly the lower levels in COVID-19 recovered patients and higher levels in prostate cancer patients, suggest unique neutrophil activities and immune responses. These insights into neutrophil-mediated immunosuppression and inflammation could inform the development of targeted therapies for infections, cancer, and autoimmune diseases. Further research is needed to elucidate the specific mechanisms underlying neutrophil-induced immunosuppression.

Arginase activity and arginine metabolism in immune cells have important consequences for health and disease. Their dysregulation is commonly observed in cancer, autoimmune disorders and infectious diseases. Following the initial description of a role for arginase in the dysfunction of T cells mounting an antitumour response, numerous studies have broadened our understanding of the regulation and expression of arginases and their integration with other metabolic pathways. Here, we highlight the differences in arginase compartmentalization and storage between humans and rodents that should be taken into consideration when assessing the effects of arginase activity. We detail the roles of arginases, arginine and its metabolites in immune cells and their effects in the context of cancer, autoimmunity and infectious disease. Finally, we explore potential therapeutic strategies targeting arginases and arginine.

Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study.

We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels.

This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development.

Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Noncystic fibrosis bronchiectasis, hereafter referred to as bronchiectasis, is a chronic, progressive lung disease that can affect people of all ages. Patients with clinically significant bronchiectasis have chronic cough and sputum production, as well as recurrent respiratory infections, fatigue and impaired health-related quality of life. The pathophysiology of bronchiectasis has been described as a vicious vortex of chronic inflammation, recurring airway infection, impaired mucociliary clearance and progressive lung damage that promotes the development and progression of the disease. This review describes the pivotal role of neutrophil-driven inflammation in the pathogenesis and progression of bronchiectasis. Delayed neutrophil apoptosis and increased necrosis enhance dysregulated inflammation in bronchiectasis and failure to resolve this contributes to chronic, sustained inflammation. The excessive release of neutrophil serine proteases, such as neutrophil elastase, cathepsin G and proteinase 3, promotes a protease-antiprotease imbalance that correlates with increased inflammation in bronchiectasis and contributes to disease progression. While there are currently no licensed therapies to treat bronchiectasis, this review will explore the evolving evidence for neutrophilic inflammation as a novel treatment target with meaningful clinical benefits.

Inflammatory bowel disease (IBD) involves a range of immune-mediated disorders marked by systemic and local intestinal inflammation. We synthesized a novel compound DJ-X-025 and uncovered its anti-inflammatory properties using lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and a dextran sodium sulfate (DSS)-induced model of colitis.

We evaluated the alteration in cell morphology, cytoskeletal proteins, and inflammatory markers of DJ-X-025 treated LPS-stimulated RAW 264.7 macrophages. We administered DJ-X-025 by oral gavage in DSS-induced colitis, examined colon histology, and alterations of immune cells by flow cytometry, and performed molecular studies using RT-qPCR and western blot analysis. DJ-X-025 treatment markedly altered the morphology of LPS-treated RAW 264.7 macrophages from elongated to round shapes, modulated actin and tubulin, and reduced the level of inflammatory markers like TNF-α, IL-1β, IL-6, and iNOS. Further, we observed that DJ-X-025 steered to improve colon length, muscularis mucosa thickness, and colon inflammatory score compared to the DSS group alone. DJ-X-025 effectively inverted the increased population of activated T cells, Th17, and macrophages in lamina propria by DSS treatment, leading to a substantial reduction in the inflammatory response in the colon. Strikingly, DJ-X-025 treatment enhanced the expression of occludin and diminished the expression of NF-κB and phosphorylation of STAT3 in the colon of DSS-treated mice compared to DSS-alone. Additionally, DJ-X-025 induced the expression of Foxp3 in the colon and, reduced systemic inflammatory cytokine/chemokine levels further supporting its immunomodulatory effects. These results suggest that DJ-X-025 is linked to the induction of occludin expression and decreased expression of p-STAT3/NF-κB and Th17 response in the colon, which together suppresses systemic and colon inflammatory cytokines for effective amelioration of experimental colitis.

These findings suggest that DJ-X-025 might be a promising therapeutic agent for the treatment of IBD.

Wound healing remains a critical global healthcare challenge, with an annual treatment cost exceeding $50 billion worldwide. Over the past decade, significant advances in wound care have focused on developing sophisticated biomaterials that promote tissue regeneration and prevent complications. Despite these developments, there remains a crucial need for multifunctional wound healing materials that can effectively address the complex, multiphase nature of wound repair while being cost effective and easily applicable in various clinical settings. This review systematically analyzes the latest developments in wound healing materials, examining their chemical composition, structural design, and therapeutic mechanisms. We comprehensively evaluate various bioactive components, including natural polymers, synthetic matrices, and hybrid composites, along with their different forms, such as hydrogels, powders, and smart dressings. Special attention is given to emerging strategies in material design that integrate multiple therapeutic functions, including sustained drug delivery, infection prevention, and tissue regeneration promotion. The insights provided in this review illuminate the path toward next-generation wound healing materials, highlighting opportunities for developing more effective therapeutic solutions that can significantly improve patient outcomes and reduce healthcare burden.

Testicular torsion, a critical urological emergency caused by twisting of the spermatic cord, poses a risk of ischemia, particularly in children who often struggle to pinpoint symptoms onset. Delay in managing testicular torsion can lead to the need for orchiectomy. The aim of this study was to assess the association between hematologic parameters-mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP)-and testicular salvage in cases of testicular torsion. Four databases (PubMed, Embase (Ovid), Science Direct, and Scopus) were systematically searched for eligible studies published up to November 4, 2024. The primary outcome was testicular salvage. Sensitivity analysis was performed using leave- one-out plot. Subgroup analysis was performed based on age, country, region, duration to orchiopexy and duration to orchiectomy. Heterogeneity was examined using I 2 statistics, and a random-effect model was applied. Out of 363 studies identified, nine observational studies involving 796 patients were included, with 338 (42.3%) in orchiopexy group. The meta-analysis indicated that MPV value was significantly elevated in orchiectomy group (mean difference (MD): -0.4; 95% confidence interval (95%CI): -0.62-(-0.18); p < 0.01), with higher MPV levels associated with an increased likelihood of orchiectomy (odds ratio (OR): 2.12; 95%CI: 1.35-3.33; p < 0.01). NLR, PLR, and CRP showed no significant association with testicular salvage, as demonstrated by pooled MD and OR analyses (p > 0.05). No significant differences were observed after sensitivity and subgroup analysis (p > 0.05). These findings suggest that elevated MPV levels are associated with non- salvageable testis, requiring orchiectomy highlighting its potential utility in clinical evaluation for testicular torsion.