Bing Wan

Background/Objectives: Human islet amyloid polypeptide (IAPP) aggregation plays a critical role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although metabolic alterations are a hallmark of T2DM, the functional roles of differential metabolites in regulating disease-associated molecular processes remain largely unexplored. This study aimed to establish a metabolomics-guided strategy for identifying endogenous metabolites with anti-amyloid activity and to investigate their underlying chemical interactions with IAPP. Methods: Untargeted metabolomic profiling of clinical samples from T2DM patients, obesity patients and healthy controls was performed to identify differential metabolites. Candidate metabolites were subsequently screened for their ability to modulate IAPP aggregation. Transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assays, and cell viability measurements were employed to evaluate their effects on fibril formation and cytotoxicity. Mass spectrometry was further used to characterize metabolite–IAPP interactions. Results: Metabolomic analysis identified 3-hydroxypyruvic acid (also known as β-hydroxypyruvic acid, hereafter referred to as HPA) as a significantly altered endogenous metabolite associated with T2DM and a candidate regulator of IAPP aggregation. Functional assays demonstrated that HPA effectively inhibited amyloid fibril formation, as evidenced by the absence of typical fibrillar structures and a prolonged lag phase during aggregation. HPA also significantly alleviated IAPP-induced cytotoxicity. Mass spectrometric analysis revealed the formation of HPA–IAPP oligomer complexes (n < 4), suggesting that HPA directly interacts with early oligomeric intermediates and interferes with their progression toward mature fibrils. Conclusions: This work demonstrates that untargeted metabolomics of clinical samples can serve as an effective strategy for discovering bioactive endogenous metabolites involved in disease-related molecular processes. The identification of HPA as a potential endogenous inhibitor of IAPP aggregation provides new chemical insight into the relationship between metabolic dysregulation and amyloidogenesis and highlights endogenous metabolites as a valuable source of potential therapeutic lead compounds.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life‐threatening interstitial lung disorder marked by aberrant mucus hypersecretion and excessive extracellular matrix (ECM) deposition, which together severely limit the effectiveness of current therapies. Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a “traffic jam‐like” physical obstruction that severely restricts drug penetration and retention. Here, we developed dual‐enzyme‐modified inhalable nanoparticles (Lipo/PFD‐CB) by co‐functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA‐approved antifibrotic drug pirfenidone (PFD). Specifically, bromelain cleaves mucin crosslinks to reduce mucus viscosity, while collagenase degrades dense ECM fibers to facilitate deep tissue penetration and prolonged retention. This dual‐enzyme remodeling strategy significantly improved aerosol deposition efficiency (86.5%) and optimized the pharmacokinetic profile and tissue distribution of PFD. In both early and advanced bleomycin‐induced fibrosis models, Lipo/PFD‐CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme‐mediated, microenvironment‐remodeling inhalable nanoplatform that effectively “clears the pulmonary traffic jam,” restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.

Background: Patients with coexisting lung cancer and COPD are highly susceptible to unplanned readmissions. This study aimed to develop and internally validate a robust predictive nomogram based on the “inflammation-nutrition-tumor” framework to quantify this risk. Methods: A retrospective cohort of 207 clinical episodes from male patients with lung cancer and COPD was analyzed. Participants were categorized into Planned Readmission (PR, n = 165) and Unplanned Readmission (UR, n = 42) groups. Independent risk factors were identified via univariate and multivariable analyses using Generalized Estimating Equations (GEE). A nomogram was subsequently constructed, and its performance was rigorously evaluated using the Area Under the Curve (AUC), calibration plots, and Decision Curve Analysis (DCA). Results: Multivariable GEE analysis demonstrated that the Systemic Immune-Inflammation Index (SII) was a highly significant independent risk factor (OR for a 500-unit increase = 1.490, 95% CI: 1.234–1.798, p < 0.001). Advanced cancer stage (III–IV) was also a significant predictor (OR = 3.590, 95% CI: 1.301–9.909, p = 0.014), while prealbumin (OR = 0.950, 95% CI: 0.896–1.007, p = 0.087) was identified as a key nutritional predictor. The integrated four-variable nomogram (age, cancer stage, SII, prealbumin) demonstrated good discriminative ability with an AUC of 0.809 (95% CI: 0.733–0.885). The calibration plot indicated excellent agreement, and DCA confirmed a substantial clinical net benefit. Conclusions: This SII-based nomogram provides a reliable and practical tool for individualized risk stratification, facilitating targeted clinical interventions to mitigate unplanned readmission rates in this vulnerable population.

Acute exacerbations of chronic obstructive pulmonary disease (AE‑COPD) are often accompanied by systemic inflammatory responses and can lead to coagulation disorders and thrombotic complications, thereby increasing hospitalization rates and mortality. Platelets play a critical role not only in hemostasis and thrombosis, but also in immunity and inflammation. The aim of the present study was to explore the associations among thrombocytopenia, infection severity and deep vein thrombosis (DVT) formation in patients with AE‑COPD, and to develop a predictive model based on platelet‑related parameters. The clinical data from 338 patients with AE‑COPD who were hospitalized in the Department of Respiratory and Critical Care Medicine of The Affiliated Jiangning Hospital of Nanjing Medical University (Nanjing, China) between January 2021 and December 2023 were retrospectively evaluated. Demographic characteristics, medical history, comorbidities, laboratory test results, lower limb venous ultrasound findings, chest computed tomography scans and mechanical ventilation treatment data were collected. Statistical analyses were performed using SPSS version 26.0, GraphPad Prism version 9.0 and R version 4.1.3. Among the 338 patients with AE‑COPD, 72.4% were male and the mean age was 75.60±7.42 years. The thrombocytopenia group (<150x109 platelets/l) had a significantly lower white blood cell count, neutrophil count, monocyte count, platelet‑to‑lymphocyte ratio (PLR) and plateletcrit compared with the normal platelet group (≥150 to 70 years old, and presented with both cardiovascular diseases and concurrent pulmonary infection, the DVT risk was found to be lower in the thrombocytopenia group. Multivariate logistic regression analysis revealed that PLR and D‑dimer were independent risk factors for DVT formation during hospitalization in patients with AE‑COPD. In conclusion, thrombocytopenia was associated with more severe lung infections in patients with AE‑COPD. A model incorporating PLR and D‑dimer showed diagnostic efficacy for predicting DVT in hospitalized patients with AE‑COPD.

Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer, characterized by high mortality rates. KAT2A has been implicated in oncogenic processes and tumor progression. This study systematically investigated the role of KAT2A in LUAD through comprehensive analyses. Expression profiles and prognostic significance of KAT2A were evaluated using TCGA database and multiple GEO datasets. Functional enrichment analyses including GO and KEGG pathway analyses were conducted to elucidate biological mechanisms associated with KAT2A-regulated differentially expressed genes. Correlations between KAT2A expression levels and immune cell infiltration were analyzed using R software and publicly available databases. Experimental validation was performed through CCK-8 assays, colony formation assays, flow cytometry, and xenograft tumor models. Our findings demonstrated significantly elevated KAT2A expression in LUAD tissues and cells. Expression levels correlated with multiple clinicopathological parameters including TNM stage, pathological stage, sex, and tumor localization. High KAT2A expression was associated with reduced overall survival and exhibited prognostic relevance across diverse clinical subgroups. Multivariate analysis confirmed independent prognostic value of KAT2A expression in the established nomogram model. Functional annotation revealed enrichment of KAT2A-associated genes in critical biological processes and signaling pathways. Moreover, KAT2A expression exhibited correlations with mutational profiles and immune cell infiltration patterns in LUAD. Both in vitro and in vivo experiments demonstrated that KAT2A knockdown significantly suppressed tumor cell proliferation and immune evasion mechanisms, induced apoptosis, and inhibited tumor growth. These findings suggest that KAT2A may serve as a potential prognostic biomarker for LUAD, with therapeutic implications through its regulatory role in immune evasion pathways.

Background: In acute respiratory distress syndrome (ARDS), neutrophils, as the primary effector immune cells, undergo profound transcriptional and phenotypic reprogramming in response to complex inflammatory stimuli, modulating signal transduction and immune responses. Liquid-liquid phase separation (LLPS) plays a pivotal role in transcriptional dynamics and signal transduction, critically influencing gene expression stability. However, the mechanistic and clinical implications of LLPS in ARDS progression remain elusive. Materials and methods: This study systematically characterized neutrophil LLPS in ARDS through integrated single-cell transcriptomes (GSE157789), proteomes (GSE32707/GSE76293), and clinical cohorts date. LLPS-associated genes (LCGs) were screened from the PhaSepDB 2.1 database and subsequently integrated with single-cell sequencing data from Gene Expression Omnibus (GEO) to quantify neutrophil LLPS scores and divide patient stratification into high and low LLPS groups for differential expression analysis of critical LCGs and associated pathways. Phase-separated droplets were then isolated from peripheral blood neutrophils of ARDS patients and N-formylmethionyl-leucyl-phenylalanine (fMLP) -stimulated neutrophils, followed by proteomic identification of droplet-associated proteins and candidate gene selection through GEO data analysis. The prognostic value of LLPS scores and candidate genes was subsequently validated in clinical cohorts, while the relationship between phase separation of candidate genes and cellular function was experimentally confirmed through immunofluorescence, Western blotting, and complementary functional assays. Results: Neutrophils in ARDS exhibit elevated LLPS scores ( p p =0.0119) but inversely with SOFA scores (r=-0.8896, p =0.0433). Patients with high LLPS scores demonstrated significantly improved overall survival ( p =0.046), suggesting a protective role of LLPS in ARDS pathogenesis. Mechanistically, the chemoattractant fMLP triggers reversible MYL12A phase separation via phosphorylation at Ser19, thereby potentiating neutrophil migratory capacity. Conclusions: This study demonstrates that LLPS dynamically regulates neutrophil migration through MYL12A phosphorylation-dependent phase separation, exerting immunoprotective effect in ARDS. The LLPS status of MYL12A and its activity score may serve as ARDS prognostic biomarkers and offer a novel strategy for developing LLPS-targeted immunomodulatory therapies.

Hyperinflammatory response in early stage of sepsis was the key factor leading to multi-organ injury. Therefore, exploring an effective therapy to attenuate or reverse hyperinflammation was the priority of sepsis treatment. Previous study from our team showed that recombinant human interleukin-11 (rhIL-11) was a promising anti-inflammation cytokine in sepsis. However, the molecular mechanism was not fully elucidated. This study aims to evaluate the therapeutic potential of rhIL-11 in septic mice model and explore the underlying the molecular mechanism. A cecal ligation and puncture (CLP) model was applied to induce septic mice. Mice were separated into five groups with six animals in each group, including normal, sham, sham + rhIL-11, CLP and CLP + rhIL-11 groups. Therapeutic potential of rhIL-11 was evaluated by comparing body weight, survival time and liver damage (hematoxylin and eosin (H&E) staining, pro-inflammatory cytokines and serum measurements of liver enzymes). Hepatic myeloid-derived suppressor cells (MDSC) percentage was also compared. In vitro, MDSC differentiation from bone marrow (BM) cells was induced in the presence of appropriate stimuli, followed by the proportion and subsets analysis via flow cytometer. The related signal pathways including STAT3 and mTORC1 were detected by western blotting. The effect of MDSCs inhibition by STAT3 and mTORC1 inhibitors on septic mice was evaluated by comparing survival time, liver damage and MDSCs percentage. Here, we declared that early treatment of rhIL-11 exerted a liver protective effect and caused the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) in septic mice model. The results of in vitro studies declared that rhIL-11 promoted differentiation of BM cells into M-MDSCs phenotypically and functionally via activating STAT3 signaling, which was cross-regulated by the mTORC1. Furthermore, we also elucidated that mTORC1 bound directly to STAT3 through an interaction between raptor and TOS motif in STAT3. Finally, inhibition of mTORC1 or STAT3 in vivo blocked the differentiation of M-MDSCs and attenuated liver protective effect of rhIL-11. Taken together, these results suggested that early treatment of rhIL-11 in septic mice might reverse the hepatic damage at least in part by inducing the differentiation of M-MDSCs via STAT3 signaling pathway, and STAT3 signaling is modulated by a parallel branch of mTORC1.

Liquid-liquid phase separation (LLPS) is integral to various biological processes, facilitating signal transduction by creating a condensed, membrane-less environment that plays crucial roles in diverse physiological and pathological processes. Recent evidence has underscored the significance of LLPS in human health and disease. However, its implications in respiratory diseases remain poorly understood. This review explores current insights into the mechanisms and biological roles of LLPS, focusing particularly on its relevance to respiratory diseases, aiming to deepen our understanding and propose a new paradigm for studying phase separation in this context.