Aneurysmal subarachnoid hemorrhage (aSAH) confers substantial mortality and morbidity driven not only by primary brain injury but also by systemic remote organ complications across the pulmonary, cardiac, renal and gastrointestinal systems. Despite growing recognition of neuroimmune crosstalk in this process, a cohesive, systems-level model connecting intracranial hemorrhage to multi-organ dysfunction remains absent from the literature. Here, we propose a unified neuroimmune framework centered on a long-underappreciated mechanism: glymphatic and meningeal lymphatic drainage dysfunction is hypothesized to act as the upstream initiating event that forces brain-derived damage-associated molecular patterns, inflammatory cytokines and activated immune cells to spill into the systemic circulation. We systematically map three mechanistically distinct, mutually amplifying transmission pathways: the classical neuroendocrine-immune axis, the recently identified meningeal lymphatic-deep cervical lymph node immune drainage axis, and circulating humoral effectors exemplified by neutrophil extracellular traps. Most notably, we integrate these pathways with a temporally stratified immune continuum spanning early hyperinflammatory SIRS, stroke-induced immunodepression, and chronic low-grade inflammation - an integrative temporal architecture that has eluded prior single-organ or single-pathway studies. Grounded in this framework, we put forward a tiered, phase-specific neuroimmunomodulatory strategy that simultaneously addresses central inflammatory origins, systemic signal propagation, and end-organ tissue damage. By reframing remote organ injury as a time-dependent immune process rather than a collection of isolated organ complications, this work provides a mechanistic and translational roadmap for time-stratified clinical trials and redefines the investigative direction for multi-organ management in aSAH.
Cancer treatment has dramatically improved with the introduction of immune checkpoint inhibitors (ICIs). They are now common treatments for individuals of reproductive age, an important consideration when treating pregnant patients. Cancer in pregnancy is rare and guidelines available for ICI use during gestation are based on pre-clinical studies, single human case reports and spontaneous report databases. The immune pathways including PD-1 and PD-L1/PD-L2 and CTLA-4 provide critical immune inhibitory checkpoints at the maternal-fetal interface. These pathways support immune tolerance during implantation and the development of the placenta. Experimental animal studies demonstrated that inhibiting these immune pathways will result in increased frequency of adverse events such as spontaneous abortions and premature births. Human placental transfer of ICIs across the placenta is minimal in early gestation and increases in later gestation, coinciding with less exposure to developing organs during organogenesis and more exposure closer to term. There are now seventeen documented cases in the literature describing pregnant patients treated with ICIs. Most neonates developed normally in infancy, while there are a few documented cases of suspected neonatal immune-mediated complications. Experts including regulatory agencies and oncology professional organisations advise against the use of ICIs in pregnancy unless their use is critical to the survival of the patient and there is no safer alternative. Patient counselling regarding the risks of using ICIs during pregnancy, postpartum or both, involves a multidisciplinary team and requires shared decision making regarding maternal health, infant follow-up and standardised documentation for understanding potential delayed effects on neonate immunity as well as providing accurate information for future counselling.
Sepsis and acute kidney injury (AKI) are life-threatening conditions often coexisting as sepsis-associated AKI (S-AKI). However, their shared molecular mechanisms and immune heterogeneity remain unclear. This study aims to identify robust diagnostic biomarkers applicable to both conditions and to elucidate their diverse immune microenvironments using integrated transcriptomic approaches. Transcriptomic datasets for sepsis and AKI were analyzed, with multiple cohorts used for training and external validation. Differential gene expression and WGCNA identified key modules, while LASSO and Random Forest algorithms screened shared hub genes. A diagnostic nomogram was constructed and evaluated using ROC and decision curve analyses. Single-cell RNA sequencing data were further analyzed to determine cellular localization, functional pathways, and intercellular communication. Four hub genes (FBXO21, FLOT1, TMC6, and KLRB1) were identified as robust diagnostic biomarkers for both sepsis and AKI, demonstrating strong predictive performance across validation cohorts. Single-cell analysis revealed that these genes were enriched in specific immune cell populations and injured renal cells, and were closely associated with T-cell activation and immune signaling pathways. Cell-cell communication analysis further inferred distinct ligand-receptor interactions that may underlie immune crosstalk in both conditions. We identified a reliable four-gene diagnostic signature shared by sepsis and AKI and characterized their shared immune heterogeneity and inferred intercellular communication networks. These findings provide potential targets for early diagnosis and therapeutic intervention in sepsis-associated renal injury.
Anthracyclines such as doxorubicin remain central to cancer therapy, but their clinical utility is constrained by dose-limiting cardiotoxicity and long-term cardiovascular sequelae. Although traditionally attributed to cardiomyocyte-intrinsic mechanisms, including mitochondrial dysfunction, oxidative stress, and DNA damage, emerging evidence demonstrates that these initial injuries rapidly activate the immune system, transforming doxorubicin-induced cardiotoxicity (DIC) into a multicellular inflammatory process. Release of mitochondrial and nuclear danger signals triggers innate immune pathways and recruitment of neutrophils, monocytes, and lymphocytes, whose sustained activation promotes maladaptive remodeling, fibrosis, and chronic dysfunction. Conversely, specific immune subsets exert context-dependent cardioprotective effects, underscoring the dual role of immune responses in disease progression. This review frames DIC within a cardioimmunology paradigm, highlighting the intersection of mitochondrial stress, sterile inflammation, and adaptive immunity across acute and chronic phases of injury. We discuss emerging therapeutic strategies that extend beyond cardiomyocyte protection, including immune recalibration rather than broad immunosuppression, immune-targeted interventions, and biomarker-guided monitoring, to enable mechanism-based, individualized cardioprotection without compromising anticancer efficacy.
The present study evaluated the effects of dietary Ocimum gratissimum leaf extract (OGE) on growth performance, haemato-biochemical responses, immune status, and tissue integrity in Labeo rohita (Hamilton, 1822). Among different solvent fractions, ethanol and acetone extracts exhibited superior antibacterial activity against major fish pathogenic bacteria. The ethanolic extract demonstrated strong bactericidal activity against Edwardsiella piscicida, Aeromonas veronii, A. sobria, Serratia nematodiphilia, and Pseudomonas putida, with minimum inhibitory concentrations ranging from 0.0078 to 0.0156 mg mL-1. Time-kill kinetics further confirmed concentration- and time-dependent antibacterial effects, with ≥ 3× MIC producing marked reductions in viable bacterial counts. A 90-day dose standardisation feeding trial using graded dietary inclusion levels of OGE (1×-4× MIC) identified supplementation at 3× MIC for 60 days as the optimum regimen for sustained enhancement of innate immune and antioxidant responses in L. rohita. Fish fed the 3× MIC diet exhibited markedly higher respiratory burst activity, ceruloplasmin, antiprotease activity, myeloperoxidase, and ferric reducing antioxidant power (FRAP). Dietary OGE supplementation markedly improved growth performance, including final body weight, weight gain, specific growth rate, and feed conversion ratio. Haematological indices showed no adverse changes during the feeding phase but improved significantly following A. veronii challenge, with elevated RBC, WBC, haemoglobin, and packed cell volume in OGE-fed group. Serum biochemical analyses revealed transient elevations of glucose, cholesterol, total protein, ALT, AST, LDH, and CRP in OGE-fed fish, accompanied by faster recovery towards basal levels following infection. Dietary OGE supplementation also improved post-challenge survival against A. veronii infection, resulting in a relative percent survival (RPS) of 71.4%. Histopathological severity scoring further demonstrated significantly reduced renal and hepatic lesion scores in OGE-fed fish, whereas the positive control group developed progressive lesions characterised by tubular degeneration, glomerulonephritis, hepatocellular necrosis, vacuolation, and cellular hypertrophy. Overall, dietary supplementation with OGE at 3× MIC for 60 days effectively enhanced growth, immune competence, antioxidant defence, haemato-biochemical stability, and tissue integrity in L. rohita, highlighting its potential as a sustainable phytogenic feed additive in aquaculture.
Intestinal epithelial cells play a crucial role in teleost defence against complex aquatic environments. However, the study of intestinal mucosal immunity in teleosts has been hindered by the lack of reliable and specific marker genes to distinguish between different cell types. In this study, single-cell RNA-seq analysis of the intestinal epithelial cells from healthy and infected Sebastes schlegeli was performed to investigate the heterogeneity of teleost intestinal epithelial cells. Immune cells, including T cells, B cells, non-specific cytotoxic cells (NCCs) and myeloid cells, and non-immune cells including enterocyte, erythrocyte, BEST4+ cell, goblet cell and enteroendocrine cell, were identified. Several notable cell populations, including early myeloid cells, lysosome-rich enterocytes, enterocyte progenitors and BEST4+ cells, were characterized in detail. Additionally, significant changes in the expression of actin polymerization-related genes were observed in various intestinal mucosal cell types following Edwardsiella piscicida infection, suggesting a mechanism of invasion with E. piscicida. These findings enhance our understanding of teleost intestinal cellular composition and provide valuable insights for the development of therapeutic strategies against E. piscicida.
Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear. This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis. We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction. Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3+ T cells (432 [173-1,381] vs 121 [43-400] cells/mm2; P = 0.036), CD8+ T cells (289 [73-994] vs 86 [21-168] cells/mm2; P = 0.019), and CD 68+ macrophages (307 [116-841] vs 57 [36-200] cells/mm2; P = 0.008); and higher CD4+ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall. Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.
Metastasis remains a leading cause of mortality in esophageal squamous cell carcinoma (ESCC) patients, underscoring the urgent need to elucidate the molecular mechanisms driving disease progression. In this study, we delineated that ZBED2, a zinc finger protein, correlates with inferior survival outcomes and metastasis in ESCC patients. ZBED2 formed phase-separated nuclear condensates that functionally promote tumor metastasis, and integrin-linked kinase (ILK) was pinpointed as a critical downstream effector in mediating the pro-metastatic function of ZBED2. Mechanistically, ZBED2 enhanced the transcription of HSP90AA1, promoted the physical interaction between HSP90AA1 and ILK, and consequently stabilized ILK by suppressing its ubiquitination. Subsequently, ILK promoted PD-L1 transcription and CD8+ T cell exhaustion, thereby creating an immunosuppressive microenvironment that facilitates cancer metastasis. Collectively, these findings establish the pivotal role of ZBED2 in driving ESCC metastasis and immune evasion, thereby validating it as a promising therapeutic target for this aggressive malignancy.
Central nervous system (CNS) immune reconstitution inflammatory syndrome (IRIS) is well characterized in HIV but exceedingly rare in pediatric hematologic malignancies. An 11.5-year-old girl with acute myeloid leukemia (AML) and probable invasive pulmonary mold infection developed an expansive right parieto-occipital lesion with a 14 mm midline shift during neutrophil recovery. Evaluation excluded leukemic infiltration and active infection. Probable CNS IRIS was diagnosed; dexamethasone with continued antifungal therapy produced rapid clinical and radiologic recovery, with sustained AML remission at 29 months. CNS IRIS should be considered in pediatric AML with unexplained neurological deterioration during neutrophil recovery; timely corticosteroid therapy can be life-saving.
Lung cancer is one of the most lethal malignancies, with non-small cell lung cancer (NSCLC) being the most common histologic subtype. Metastasis leads to poor prognosis for patients with cancer. Tumor cells leave the tumor lesions, invade the surrounding stroma, and enter the bloodstream as circulating tumor cells (CTCs). The development of CTCs is the beginning of metastasis. The internal environment in which tumor cells grow and survive is called the tumor microenvironment (TME). It includes tumor cells, fibroblasts, immune cells, and the extracellular matrix. The TME is complex and dynamic. Moreover, the TME plays an important role in tumor development and metastasis and significantly impacts therapeutic outcomes. Immune checkpoint blockade (ICB) aims to inhibit the interaction of ligands with their corresponding receptors. ICB has the function of restoring the anti-tumor effect of immune cells. This review examines how TME interacts with CTCs, allowing CTCs to evade immunity and facilitating CTC metastasis. TME not only affects the progression of tumor metastasis but also interacts with tumor cells, which may affect the efficacy of immunotherapy.
Atopic dermatitis (AD) and psoriasis (PSO) are chronic inflammatory skin diseases that impose substantial physical and psychological burdens. Although fungal-bacterial balance is important for skin immune homeostasis, the role of the skin mycobiome and its interaction with bacterial communities and host immunity in these diseases remains poorly understood. To characterize alterations in the skin mycobiome and its interactions with bacterial communities and host immune responses in AD and PSO. Adult patients with chronic AD, plaque-type PSO and healthy volunteers were included in this study. Skin microbiota samples and biopsies were collected from lesional and non-lesional skin areas, including the posterior thigh for AD and the lower back for PSO. Whole-metagenome shotgun sequencing was used to profile microbial communities. SparCC was used to construct fungal-bacterial co-occurrence networks, and integration of host transcriptomic and microbial features was performed using O2PLS. Both AD and PSO showed disease-associated restructuring of Malassezia species and reduced fungal-bacterial ecological connectivity in lesional skin. In AD, Malassezia arunalokei was inversely associated with Staphylococcus aureus and linked to antimicrobial peptide-centred host gene modules enriched for IL-17 signalling. Its abundance decreased with increasing disease severity and inversely correlated with inflammatory immune cell signatures. In PSO, altered Malassezia composition was associated with IL-17-driven transcriptional programmes and lipid metabolic pathways, suggesting interactions between fungal imbalance and inflammatory-metabolic processes. Our findings expand current models of skin dysbiosis beyond bacteria and suggest that disrupted fungal-bacterial interactions are linked to immune activation in AD and PSO and, in AD, to disease severity. Although further validation is required, skin microbiome features may provide clinically relevant information for disease monitoring, patient stratification and future microbiome-informed therapeutic strategies. Our study lays the groundwork for microbiome modulation as a potential therapeutic strategy for AD and PSO. Atopic dermatitis (AD) and psoriasis (PSO) are common long‐term inflammatory skin diseases that can cause itching, redness and various comorbidities, often affecting quality of life. While most previous research has focused on skin bacteria, less is known about the role of fungi and how they interact with bacteria and the human immune system. In this study, we analysed skin samples from patients with AD and PSO, as well as healthy individuals, using sequencing‐based approaches to examine both bacterial and fungal communities, together with gene expression analyses to assess immune activity in the skin. We found that in both diseases, the normal balance between fungi and bacteria is disrupted. In AD, certain fungal species that are more common in healthy skin were reduced, whereas bacteria such as Staphylococcus aureus increased and were linked to stronger immune responses and more severe disease. In PSO, changes in fungal composition were associated with inflammation and alterations in skin metabolism. These findings suggest that changes in the skin microbiome are closely linked to disease activity. Microbial patterns may help to monitor disease progression or identify patients at higher risk of worsening symptoms. In the future, treatments that combine immune‐targeted therapies with approaches to restore microbial balance may offer more personalized ways to manage these conditions.
The COVID-19 pandemic posed significant mental and physical challenges for healthcare professionals (HCPs), leading to increased stress and potential immune dysregulation. Yoga practice, has been suggested to enhance immunity and alleviate stress. This pilot study aimed to assess the impact of yoga intervention on immune markers, stress levels, and quality of life among HCPs actively working during the pandemic. A single-center, open label randomized controlled pilot study was conducted at tertiary care centre, with 36 participants. Physicians were randomly assigned to either a yoga intervention group (n=18) or a control group (n=18). The intervention included guided online yoga sessions for 12 weeks. Immunological markers (IL-6, IL-12, CRP, INF-gamma, TNF-alpha) were measured using ELISA at baseline and post-intervention. Stress levels and quality of life were assessed using the WHO-BREF questionnaire. Statistical analysis was performed Microsoft excel M365 software, employing t-tests. Significant improvements were observed in immune markers, particularly a reduction in IL-12 (p=0.0165) and CRP (p=0.001), alongside a marked increase in INF-gamma (p=0.001) in the yoga group. BMI significantly improved (p=0.0194), though stress levels and most quality-of-life domains remained unchanged, except for social relationships (p=0.0279). Correlation analysis suggested a strong relationship between BMI reduction and immune modulation. Yoga intervention demonstrated potential benefits in modulating immunological markers and improving BMI among physicians. While stress reduction was not significant, enhanced social relationships and immune function suggest yoga as a complementary approach for HCPs well-being during high-stress periods. Further large-scale studies are recommended to validate these findings.
Prostate cancer (PCa) remains a major clinical challenge due to therapeutic resistance and immunologically cold tumor microenvironment. Lysosomal membrane permeabilization (LMP)-induced lysosome-dependent cell death offers an alternative route to eliminate resistant tumor cells and initiate immunogenic cell death, yet its efficacy is often limited by insufficient spatiotemporal control and immune activation. Here, we report a spatiotemporally programmable supramolecular nanoplatform (Cu-P-MSA) that integrates lysosome-targeted sonodynamic therapy with tumor-confined innate immune activation for PCa treatment. Cu-P-MSA is a modular self-assembling peptide incorporating a PSMA-targeting ligand, morpholine moiety, and cathepsin B-cleavable linker, enabling tumor-selective uptake and in situ formation of fibrous sonosensitizer depots within lysosomes. Upon ultrasound irradiation, a glutathione-responsive open-shell sonosensitizer induces controlled LMP, simultaneously activating ferroptosis and pyroptosis and promoting immunogenic cell death. Meanwhile, tumor-specific release of a STING agonist MSA-2 elicits robust type I interferon responses, driving dendritic cell maturation and cytotoxic T-cell infiltration. This coordinated lysosomal disruption-immune amplification strategy effectively reprograms the tumor immune microenvironment and suppresses both primary and distant tumors, with inhibition rates reaching 84.3% and 77.5%, respectively. Overall, this work establishes a spatiotemporally controlled supramolecular approach that integrates lysosomal disruption with innate immune activation to overcome therapeutic resistance and immunosuppression in PCa.
This study aimed to investigate the involvement of the Wnt signalling pathway in the pathogenesis of non-obstructive azoospermia (NOA) and to identify potential diagnostic and therapeutic targets. We obtained the gene expression profiles of NOA patients from the GEO database, screened for differentially expressed genes (DEGs) and NOA-associated co-expressing gene modules, then intersected the DEGs with related genes in the Wnt signalling pathway and identified key genes. LASSO regression analysis was used to find hub genes, and qRT-PCR and WB methods were used to verify the expression of key genes in NOA patients. The immune infiltration and GSEA were conducted in order to investigate the relationship between hub genes and immune cells infiltration and NOA-associated pathways; furthermore, we built the miRNA-mRNA-TF regulatory network and predicted possible small molecules drug targets of the hub gene. Four candidate genes were related to NOA: CSNK1G2, GNG3, H2AFB1 and PARD6A. The key hub gene was CSNK1G2 based on the results of the LASSO regression analysis, and its expression level was significantly down-regulated in NOA patients. The immune infiltration analysis and GSEA results showed that the expression level of CSNK1G2 had a close relationship with immune cells infiltration and NOA-related pathways. Furthermore, we built a miRNA-mRNA-TF regulatory network and predicted the possible small molecule drugs of CSNK1G2. Our findings suggest that the Wnt signalling pathway, particularly CSNK1G2, plays a crucial role in the pathogenesis of NOA. CSNK1G2 may be a novel target for the diagnosis and treatment of NOA.
Chronic kidney disease (CKD) is a major global health burden characterized by immune dysregulation. Peripheral blood lymphocyte subsets can reflect immune status across CKD pathologies. We evaluated associations between lymphocyte subsets and clinical parameters in patients undergoing renal biopsy in a contemporary cohort. We conducted a retrospective cross-sectional study of adults (≥16 years) who underwent native renal biopsy at Tongji Hospital, China, from January 2012 to December 2024. The lymphocyte subsets assessed by flow cytometry included combined T/B/NK cells (TBNK), total T cells (CD3+CD19-), total B cells (CD3-CD19+), helper T cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+), and natural killer cells (CD3-CD16+CD56+). Clinical data included demographics, comorbidities, medications, and clinical and immunological markers. Multivariable linear regression was employed to investigate the relationships between lymphocyte subsets as continuous variables and clinical parameters, and nested regression using quartile categories to assess dose-response relationships. In total, 1,033 individuals were enrolled. TBNK levels declined with age (β = -4.33, 95% CI: -7.35 to -1.32) and were lower in females than males (β = -84.26, 95% CI: -157.29 to -11.23). Lymphocyte subset distributions varied by nephritis pathology: ANCA-GN and lupus nephritis showed lower levels than other types, whereas purpura nephritis was relatively higher. TBNK counts correlated positively with estimated glomerular filtration rate (β = 11.48, 95% CI: 6.78 to 16.19), with similar patterns for total B, total T, CD4+ T, and CD8+ T cells. Lymphocyte counts were also positively associated with complement 3. Among IgA nephropathy, TBNK levels correlated positively with IgA (β = 0.31, 95% CI: 0.06 to 0.57) and complement 3 (β = 0.10, 95% CI: 0.06 to 0.14). Lymphocyte and subset counts relate to renal function, immune indices, and pathology. Their measurement may help evaluate disease severity and immune status in nephritis and inform clinical management.
Systemic lupus erythematosus (SLE) is a prevalent autoimmune disease affecting up to a quarter million Americans. Lupus nephritis (LN) is an immune complex glomerulonephritis that occurs when circulating immune complexes deposit in the kidney and is a common sequela of SLE. LN serves as a marker of disease severity and contributes significantly to mortality in SLE. Despite growing access to novel therapies, the disease burden remains high, and the gap between real-life challenges and clinical trial success persists. Our study is an effort to bridge the gap by examining factors such as diverse choice of immunosuppression, socioeconomic constraints, and adherence outside the carefully calibrated environment of clinical trials. We conducted a retrospective review of patients with biopsy proven LN to evaluate prognostic factors and treatment related complications at a tertiary hospital with patients selected from biopsy records obtained from January 2015 through December 2023. A total of 66 patients met inclusion criteria and were included in the final analysis of the cohort. Patients with findings other than confirmed LN and kidney transplant recipients were excluded. Longitudinal data were collected at 6 months, 12 months, 2 years, and 5 years after biopsy, and response to treatment was defined using Kidney Disease Improving Global Outcomes (KDIGO) 2024 clinical practice guidelines for LN. Of the 163 kidney biopsy reports reviewed from January 2015 through December 2023, 66 were confirmed as LN and included in the analysis. The median age at biopsy was 35 years, 76% were women, and 62% were African American. At 6 months, 50% of Class I and II LN, 49% of Class III, IV, III + V and IV + V LN, and 83% of Class V LN had no response to treatment, without significant differences between classes or in terms of partial vs. complete response. At 12 months, 55% of Class I and II, 50% of Class III, IV, III + V, and IV + V, and 87% of Class V LN had no response to treatment, with a significant difference (p = 0.04) between classes in terms of rate of response, but not in terms of partial vs. complete response. Notable complications were advancement to ESRD in 11 patients (17%), infections that required hospital admission in 27 patients (41%), and death in 9 patients (14%) in the study period. Our study provides practical and real-world data on management of LN. In patients with SLE, LN is associated with significant morbidity and mortality. Management continues to pose a unique challenge despite developing therapies. Sustained remission is often dependent on a complex interplay of individualized care, patient adherence, and socioeconomic factors. There is a need for increased awareness of LN as early biopsy, prompt initiation and continuation of treatment positively impacts outcomes.
Chronic cough, particularly prevalent in post-COVID condition (PCC, also known as long COVID), remains a significant medical challenge. Recently, extracellular vesicles (EVs) have gained significant attention for their therapeutic potential. In this study, we explore the therapeutic effects of EVs derived from mesenchymal stem cells (MSCs) cultured in a 3D system (3D-EVs) in treating chronic cough, with a focus on post-COVID-19 patients. Our in vitro experiments demonstrated that 3D-EVs promote angiogenesis and cell migration, crucial processes in tissue repair and regeneration. Notably, 3D-EVs exhibited a robust suppressive effect on lymphocyte proliferation in human PBMCs, indicating their potential immunomodulatory role. At day 6, nebulized 3D-EVs treatment group showed significantly higher rates of significant improvement (22.5% vs. 5.0%, P = 0.023) and total effectiveness (67.5% vs. 47.5%, P = 0.035), as well as a shorter mean time to cough resolution (13.83 vs. 19.90 days, P = 0.037). By day 14, total effective rates were comparable (85% vs. 80%, P > 0.05). No safety concerns were observed. RNA sequencing revealed altered B cell receptor signaling and downregulation of the mitotic cell cycle pathway, while exploratory immunophenotyping identified a significant reduction in plasma cells (P < 0.05) and directional trends in other immune subsets, providing preliminary evidence that 3D-EVs may modulate B cell differentiation and immune responses. These findings demonstrate the feasibility and preliminary efficacy of 3D-EVs for rapid relief of post-COVID-19 chronic cough, supporting larger controlled trials to validate their role in this and related respiratory diseases.
Chicken infectious anemia virus (CIAV) is a major immunosuppressive pathogen of poultry, causing aplastic anaemia, lymphoid atrophy, and severe haematopoietic dysfunction in young chicks, thereby posing a substantial threat to global poultry health and production. In this study, a novel highly pathogenic CIAV strain, designated CIAV-GDHY230813, was isolated from young Mahuang chickens in China and subjected to comprehensive molecular and pathogenic characterization. Whole-genome sequencing and phylogenetic analysis revealed that CIAV-GDHY230813 belongs to I-a branch. Notably, the VP1 protein harbored a glutamine residue at position 394, a molecular marker strongly associated with high virulence, together with multiple amino acid substitutions, insertions, and deletions across the coding regions. Pathogenicity experiments in specific-pathogen-free (SPF) chicks demonstrated that infection with CIAV-GDHY230813 resulted in pronounced growth retardation, severe damage to immune organs, and increased mortality. From 3 to 21 days post-infection (dpi), body weights of infected chicks were significantly lower than those of the control group (p < 0.01). Marked thymic and bursal atrophy, splenomegaly, and significantly reduced haematocrit levels were observed, indicating severe anaemia. Furthermore, CIAV infection led to a marked reduction in antibody titres against Newcastle disease virus vaccination by 4-fold to 8-fold, reflecting substantial suppression of humoral immune responses. Quantitative analysis of viral distribution showed significantly elevated viral loads in blood, liver, thymus, spleen, and bursa of Fabricius at both 14 and 21 dpi (p < 0.001), with peak levels detected at 21 dpi. Collectively, these findings demonstrate the strong replicative capacity and high pathogenic potential of CIAV-GDHY230813, providing valuable insights into the molecular epidemiology and pathogenic mechanisms of CIAV in China, supporting improved surveillance and control strategies, and laying a solid foundation for the development of effective vaccines against CIAV.
To identify predictive metabolic biomarkers for immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICIs) using metabolomics, supporting early detection and intervention. Fifty-five ICI-treated cancer patients from Changxing People's Hospital were divided into irAEs-positive (34 cases) and irAEs-negative (21 cases) groups after 12-month follow-up. Pretreatment serum samples were analyzed by untargeted UPLC-MS metabolomics. PCA, OPLS-DA, and KEGG pathway enrichment were used to screen differential metabolites and key pathways. Seventy significant differential metabolites (eg, ursodeoxycholic acid, uric acid) were identified. β-Alanine metabolism, pentose phosphate pathway, and coenzyme A biosynthesis were closely correlated with irAEs. Five metabolites showed AUC 0.7-0.9 with favorable predictive performance. Metabolomics reveals specific metabolites and metabolic pathways linked to ICI-induced irAEs, providing potential biomarkers for early prediction and new insights into irAEs pathogenesis to optimize clinical management.
Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.