Chronic obstructive pulmonary disease (COPD) is a global public-health concern due to its currently high morbidity and mortality. Cigarette smoke (CS) exposure, the primary inducer of COPD, can provoke ferroptosis in lung epithelial cells. Melatonin, a neurohormone, has potential anti-inflammatory and anti-oxidative capacities. In this study, we investigated the protective effects of melatonin on CS exposure-induced COPD mice, and its underlying mechanisms of actions. The results showed that CS exposure caused obvious lipid peroxidation and the accumulation of ferrous (Fe2+) with the decreased expression of melatonin receptor (MT), thus triggered ferroptosis of lung epithelial cells in vitro and in vivo. In vitro, melatonin upregulated xCT, GPX4 and ferritin (FTH1/FTL) expression, reversed the CSE-induced ferroptosis depending on activated MT with the elevated phosphorylation of cAMP response element-binding protein (CREBser133). CREB knockdown (KD) caused melatonin failure to upregulate GPX4 and FTH1/FTL expression, thus did not inhibit CSE-induced ferroptosis of airway epithelial cells. Moreover, after suppressing the transcriptional regulation of p-CREB, melatonin again failed to promote GPX4 and FTH1/FTL expression and inhibit CSE-induced ferroptosis. The mechanistic dissection showed that melatonin led to the nuclear translocation of p-CREB which in turn bound to the promoter regions of GPX4 and FTH1/FTL genes, promoted their expression. In CS-induced COPD mice, melatonin alleviated pulmonary inflammation, emphysema and airway remodeling, improved lung function via activating the CREB-GPX4/ferritin signaling axis and inhibiting ferroptosis of pulmonary epithelial cells. Taken together, our findings indicates that melatonin inhibits CS-induced ferroptosis via activating CREB-GPX4/ferritin axis depending on activated MT. These findings can help lead to promising protective strategies for COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with limited clinical therapeutic effects to suspend its progression. Circular RNAs (circRNAs) possess regulatory effects in various diseases. However, circRNA-involved regulatory mechanisms in COPD are largely unknown. This study reveals the mechanism of SMURF1-mediated BECN1 ubiquitination, which is competed by Ub-K48 and Ub-K63, driving the circPDE4D-regulated autophagy. Here, circPDE4D is first identified as a downregulated circRNA in COPD. Among patients with COPD, the lower expression of circPDE4D is associated with the reduced lung function values of FEV1/FVC%, FEV1%, and MMEF75/25% predicted. Moreover, circPDE4D promotes autophagy and SG formation, as well as relieves inflammation in vitro and in vivo. Mechanistically, circPDE4D binds with miR545-3p to regulate SMURF1, which functions in apoptosis, autophagy, SG formation, and inflammation. Importantly, SMURF1 interacts with BECN1 to form a complex and recruits Ub-K63 to enhance K63-linked ubiquitination of BECN1, whereas it antagonizes Ub-K48 to govern BECN1 stability. In particular, circPDE4D is indispensable for the SMURF1-induced BECN1 ubiquitination and can enhance the stability of BECN1. Together, this circPDE4D-miR545-3p-SMURF1-BECN1 regulatory feedback loop underlies the circPDE4D-mediated functions and provides valuable insights into the therapeutic application potential of COPD drugs and biomarkers developed based on circPDE4D.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by chronic airway inflammation and hypoxia, which is closely related to lactylation. However, the molecular mechanism of COPD involving this process remains unclear. Here, we initially found that the expression levels of core glycolytic molecules, including HK2, GLUT1, and PKM2, were significantly increased in lung tissues from patients with COPD and CS-induced COPD model, cigarette smoke extract (CSE)-exposed HBECs and BEAS-2B cells. We further observed that lactate dehydrogenase A (LDHA) expression and lactate levels were significantly elevated under the same conditions mentioned above. Notably, lactate levels were negatively correlated with FEV1/FVC across all participants. Elevated LDHA promoted lactate accumulation, which in turn significantly increased histone lactylation, particularly histone H3 lysine 14 lactylation (H3K14la), in patients with COPD and both in vivo and in vitro models. The expressions of occludin and ZO-1, tight junction proteins, were significantly decreased in CS-induced COPD model detected by Western blotting and immunofluorescence staining. Exogenous lactate further disrupted tight junction integrity, whereas inhibition of lactate production with oxamate alleviated these alterations. Moreover, LDHA knockdown restored the expressions of occludin and ZO-1 in CSE-induced cells. Mechanistically, CUT&Tag and RNA-seq results demonstrated that H3K14la led to epithelial barrier damage through upregulation of LRP5. Furthermore, LRP5 activated β-catenin signaling and decreased the expressions of occludin and ZO-1, whereas LRP5 knockdown significantly improved epithelial barrier function. Collectively, these findings indicate that lactate-driven histone lactylation involving in the molecular mechanism of COPD via H3K14la, which may worsen epithelial barrier dysfunction in COPD.

Chronic obstructive pulmonary disease (COPD) is a characteristic chronic airway inflammatory disease that worsens over time, however, there are currently limited clinical therapeutics to suspend its progression. Circular RNAs (circRNAs), which have emerged as functional regulators in various diseases, including COPD, may server as new pharmacological targets in COPD. Here, it is identified a nuclear circRNA, circCANX, that is preferentially decreased in COPD. The linear splicing of CANX pre-mRNA, enhanced by the ADAR1-HNRNPL interaction, is responsible for the circCANX decline. Clinically, the higher circCANX expression is associated with a worse lung function index of FEV1/FVC among patients with COPD. CircCANX suppresses autophagy and stress granule (SG) formation to strengthen inflammation of COPD in vivo and in vitro. Mechanistically, circCANX recruits the tumor suppressor protein P53 (P53) mRNA and RNA helicase upstream frameshift 1 (UPF1) to form a ternary complex, which mediates P53 mRNA degradation through nonsense-mediated mRNA decay (NMD) process. Together, this study reveals an important circCANX-mediated regulatory mechanism in COPD, and provides new insights into the potential of circRNA-based drug and biomarker development for COPD.

Microplastics (MPs) induce mitochondrial dysfunction and iron accumulation, contributing to mitochondrial macroautophagy/autophagy and ferroptosis, which has increased susceptibility to the exacerbation of chronic obstructive pulmonary disease (COPD); however, the underlying mechanism remains unclear. We demonstrated that MPs intensified inflammation in COPD by enhancing autophagy-dependent ferroptosis (ADF) in vitro and in vivo. In the lung tissues of patients with COPD, the concentrations of MPs, especially polystyrene microplastics (PS-MPs), were significantly higher than that of the control group, as detected by pyrolysis gas chromatography mass spectrometry (Py-GCMS), with increased iron accumulation. The exposure to PS-MPs, 2 μm in size, resulted in their being deposited in the lungs of COPD model mice detected by optical in vivo imaging, and observed in bronchial epithelial cells traced by GFP-labeled PS-MPs. There were mitochondrial impairments accompanied by mitochondrial reactive oxygen species (mito-ROS) overproduction and significantly increased levels of lysosome biogenesis and acidification in pDHBE cells with PS-MP stimulation, triggering occurrence of ferritinophagy and enhancing ADF in COPD, which triggered acute exacerbation of COPD (AECOPD). Reestablishing autophagy-dependent ferroptosis via mitochondria-specific ROS scavenging or ferroptosis inhibition alleviated excessive inflammation and ameliorated AECOPD induced by PS-MPs. Collectively, our data initially revealed that MPs exacerbate ferroptosis via mito-ROS-mediated autophagy in COPD, which sheds light on further hazard assessments of MPs on human respiratory health and potential therapeutic agents for patients with COPD.Abbreviations: ADF: autophagy-dependent ferroptosis; AECOPD: acute exacerbation of chronic obstructive pulmonary disease; Cchord: static compliance; COPD: chronic obstructive pulmonary disease; CQ: chloroquine; CS: cigarette smoke; DEGs: differentially expressed genes; Fer-1: ferrostatin-1; FEV 0.1: forced expiratory volume in first 100 ms; FVC: forced vital capacity; GSH: glutathione; HE: hematoxylin and eosin; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; MDA: malondialdehyde; Mito-ROS: mitochondrial reactive oxygen species; MMA: methyl methacrylate; MMF: maximal mid-expiratory flow curve; MMP: mitochondrial membrane potential; MOI: multiplicity of infection; MPs: microplastics; MV: minute volume; PA: polyamide; PBS: phosphate-buffered saline; PC: polycarbonate; pDHBE: primary human bronchial epithelial cell from COPD patients; PET: polyethylene terephthalate; PIF: peak inspiratory flow; PLA: polylactic acid; pNHBE: primary normal human bronchial epithelial cell; PS-MPs: polystyrene microplastics; PVA: polyvinyl acetate; PVC: polyvinyl chloride; Py-GCMS: pyrolysis gas chromatography mass spectrometry; SEM: scanning electron microscopy; Te: expiratory times; Ti: inspiratory times; TNF/TNF-α: tumor necrosis factor.

BACKGROUND:Azvudine has become a widely used treatment for COVID-19 in China. Our study aimed to assess the real-world efficacy of azvudine in hospitalized COVID-19 patients during the omicron variant surge. METHODS:This multicenter retrospective cohort study was conducted at three hospitals, starting from December 2022. We developed a propensity-score matching (PSM) model to compare patients receiving azvudine with a control group. The primary outcome measured was a composite outcome, while secondary outcomes included all-cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. RESULTS:We enrolled a total of 7216 hospitalized COVID-19 patients, monitoring them for 28 days. Following PSM, we included 901 patients in both the azvudine group and the control group. The incidence of the composite outcome was 20.2 % in the azvudine group and 25.5 % in the control group (p = 0.007). The all-cause mortality rate was 10.0 % in the azvudine group and 13.7 % in the control group (p = 0.016). The intensive care unit admission was 15.5 % in the azvudine group and 19.6 % in the control group (p = 0.022). CONCLUSION:During the omicron epidemic in China, oral administration of azvudine was associated with a reduced risk of the composite outcome and all-cause mortality in COVID-19 patients.

Cognitive dysfunction is an essential comorbidity that contributing to the whole disease process of the individual of chronic obstructive pulmonary disease (COPD), yet its specific mechanism remains controversial due to a lack of cellular and molecular evidence. Our clinical data revealed a significant reduction in total hippocampal volume in patients with COPD, with the CA1 subfield notably smaller and associated with lung function. Long-term CS exposure caused hippocampus impairment, leading to spatial and working memory impairments in COPD model mice. CS exposure triggered ferroptosis in vivo and in vitro. Bioinformatics analysis suggested that sestrin2 is a key ferroptosis-related gene involved in cognitive impairment. Sestrin2 protein levels were consistently increased in the hippocampus of COPD model mice and CSE treated HT22 cells. Sestrin2 knockdown exacerbated ferroptosis and enhanced the down-regulation of synaptophysin and PSD95, while sestrin2 overexpression inhibited these damaging processes in vitro. This neuroprotection of sestrin2 is dependent on its binding with heterogeneous nuclear ribonucleoprotein L (HNRNPL). Moreover, sestrin2 overexpression and DFO ameliorated hippocampal impairment and neurocognitive deficits by correcting CS-induced ferroptosis and synaptic proteins alterations in vivo. Overall, our study reveals that sestrin2 improves CS-induced adverse changes in hippocampal neurons and neurobehavior, providing new insights into the molecular mechanisms underlying COPD-related cognitive dysfunction.

Abstract Background Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. Methods COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. Results The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1β attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling via MTs. Conclusions These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1β/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD. Graphical Abstract Schematic mechanisms underlying the regulatory effects of melatonin on macrophage polarization and apoptosis in IAV infection plus cigarette stimulation-induced AECOPD model.

BackgroundIn recent years, COVID-19 and tuberculosis have emerged as major infectious diseases, significantly contributing to global mortality as respiratory illnesses. There is increasing evidence of a reciprocal influence between these diseases, exacerbating their incidence, severity, and mortality rates.MethodsThis study involved retrieving COVID-19 and tuberculosis data from the GEO database and identifying common differentially expressed genes. Machine learning techniques, specifically random forest analysis, were applied to pinpoint key genes for diagnosing COVID-19. The Cibersort algorithm was employed to estimate immune cell infiltration in individuals with COVID-19. Additionally, single-cell sequencing was used to study the distribution of VNN1 within immune cells, and molecular docking provided insights into potential drugs targeting these critical prognosis genes.ResultsGMNN, SCD, and FUT7 were identified as robust diagnostic markers for COVID-19 across training and validation datasets. Importantly, VNN1 was associated with the progression of severe COVID-19, showing a strong correlation with clinical indicators and immune cell infiltration. Single-cell sequencing demonstrated a predominant distribution of VNN1 in neutrophils, and molecular docking highlighted potential pharmacological targets for VNN1.ConclusionsThis study enhances our understanding of the shared pathogenic mechanisms underlying tuberculosis and COVID-19, providing essential insights that could improve the diagnosis and treatment of severe COVID-19 cases.

Fibrosis is a prevalent pathological condition observed in various organs and tissues. It primarily arises from the excessive and abnormal accumulation of the extracellular matrix, resulting in the structural and functional impairment of tissues and organs, which can culminate in death. Many forms of fibrosis, including liver, cardiac, pulmonary, and renal fibrosis, are considered irreversible. Maternally expressed gene 3 (MEG3) is an imprinted RNA gene. Historically, the downregulation of MEG3 has been linked to tumor pathogenesis. However, recent studies indicate an emerging association of MEG3 with fibrotic diseases. In this review, we delve into the current understanding of MEG3's role in fibrosis, aiming to shed light on the molecular mechanisms of fibrosis and the potential of MEG3 as a novel therapeutic target.

PurposeAsthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation.MethodsOvalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed.ResultsDEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX.ConclusionOur present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/ 6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation.

Background Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are on the rise. While there is evidence of a link between the two diseases, the pathophysiological mechanisms they share are not fully understood.Methods In this study, the co-expressed genes of COPD and T2DM in Gene Expression Omnibus database were identified by bioinformatics method, and the functional enrichment analysis was performed. Machine learning algorithms were used to identify biomarkers. The diagnostic value of these biomarkers was assessed by receiver operating characteristic analysis, and their relationship to immune cells was investigated by immunoinfiltration analysis. Finally, real-time quantitative polymerase chain reaction was performed.Results A total of five overlapping genes were obtained, focusing on pathways associated with insulin resistance and inflammatory mediators. The machine learning method identified three biomarkers: matrix metalloproteinase 9, laminin alpha 4, and differentially expressed in normal cells and neoplasia domain containing 4 C, all of which were shown to have high diagnostic values by receiver operating characteristic analysis. Immunoinfiltration analysis showed that it was associated with a variety of immune cells. In addition, the real-time quantitative polymerase chain reaction results confirmed agreement with our bioinformatics analysis.Conclusions Our study sheds light on the common pathogenesis and biomarkers of both diseases, and these findings have potential implications for the development of new diagnostic and treatment strategies for COPD and T2DM. Key message What is already known on this topic? Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist as comorbidities. However, the exact mechanistic link between the two diseases remains complex, multifactorial, and not fully understood. What this study adds? Three biomarkers, including matrix metalloproteinase, laminin alpha 4, and differentially expressed in normal cells and neoplasia domain containing 4 C, were identified as key co-expression hub genes in COPD and T2DM. How this study might affect research, practice or policy? Future studies may benefit from incorporating a larger sample set to further explore and validate the diagnostic and therapeutic effects of these core genes.Conclusions Our study sheds light on the common pathogenesis and biomarkers of both diseases, and these findings have potential implications for the development of new diagnostic and treatment strategies for COPD and T2DM. Key message What is already known on this topic? Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist as comorbidities. However, the exact mechanistic link between the two diseases remains complex, multifactorial, and not fully understood. What this study adds? Three biomarkers, including matrix metalloproteinase, laminin alpha 4, and differentially expressed in normal cells and neoplasia domain containing 4 C, were identified as key co-expression hub genes in COPD and T2DM. How this study might affect research, practice or policy? Future studies may benefit from incorporating a larger sample set to further explore and validate the diagnostic and therapeutic effects of these core genes.

Purpose: Driver mutations inform lung adenocarcinoma (LUAD) targeted therapy. Association of histopathological attributes and molecular profiles facilitates clinically viable testing platforms. We assessed correlations between LUAD clinicopathological features, mutational landscapes, and two grading systems among Chinese cases. Methods: 79 Chinese LUAD patients undergoing resection were subjected to targeted sequencing. 68 were invasive nonmucinous adenocarcinoma (INMA), graded via: predominant histologic pattern-based grading system (P-GS) or novel IASLC grading system (I-GS). Driver mutation distributions were appraised and correlated with clinical and pathological data. Results: Compared to INMA, non-INMA exhibited smaller, well-differentiated tumors with higher mucin content. INMA grade correlated with size, lymph invasion (P-GS), and driver/EGFR mutations. Mutational spectra varied markedly between grades, with EGFR p.L858R and exon 19 deletion mutations predominating in lower grades; while high-grade P-GS tumors often harbored EGFR copy number variants and complex alterations alongside wild-type cases. I-GS upgrade of P-GS grade 2 to grade 3 was underpinned by >= 20 % high-grade regions bearing p.L858R or ALK fusions. Both systems defined tumors of distinctive phenotypic attributes and molecular genotypes. Conclusions: INMA represent larger, mucin-poor, molecularly heterogeneous LUAD with divergent grade-specific mutation profiles. Stronger predictor of clinicopathological attributes and driver mutations, P-GS stratification offers greater accuracy for molecular testing. A small panel encompassing EGFR and ALK captures the majority of P-GS grade 1/2 mutations whereas expanded panels are optimal for grade 3.

Rationale: Ferroptosis in lung epithelium and endothelium contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), a critical and often fatal condition marked by acute inflammation and elevated pulmonary vascular permeability. Despite this, there are currently no FDA-approved therapeutics specifically targeting ferroptosis for ARDS management. Methods: A screening of 259 FDA-approved drugs was conducted to identify an effective ferroptosis inhibitor in pulmonary epithelial and endothelial cells. The anti-ferroptotic and therapeutic efficacy of this screened drug was rigorously evaluated using two distinct ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). The regulatory mechanism of this drug on ferroptosis inhibition was investigated via RNA-sequencing, qRT-PCR, western blotting, IF, luciferase reporter assay, chromatin immunoprecipitation assay, limited proteolysis-mass spectrometry assay, cellular thermal shift assay, and drug affinity responsive target stability assay. Furthermore, a proof-of-concept clinical trial was conducted, wherein ARDS patients were administered with the drug as adjunctive therapy. Results: Dipyridamole (DIPY) was identified as a potent inhibitor of ferroptosis in pulmonary epithelial and endothelial cells. DIPY effectively mitigated ferroptosis and pulmonary damage in both mouse models and hAOs, primarily by downregulating heme oxygenase 1 (HMOX1). The transcription factor cAMP responsive element binding protein 1 (CREB1) was identified as a key transactivator of HMOX1, which DIPY effectively downregulated. Mechanistically, DIPY binds to and activates superoxide dismutase 1 (SOD1), which in turn inhibits the CREB1/HMOX1 pathway, thereby suppressing ferroptosis. Notably, the clinical trial further corroborated the therapeutic potential of DIPY in ARDS patients, demonstrating improved outcomes with DIPY adjunctive therapy. Conclusions: These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.

Although rapid progression and a poor prognosis in influenza A virus (IAV) infection-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV-induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV-infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV-inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1-dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV-infected pDHBE cells; however, these changes were rescued by OMA1-siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV-induced cellular energy exhaustion via OMA1-OPA1-S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV.

BACKGROUND:Acidosis is the most common complication that seriously affects the prognosis of acute respiratory distress syndrome (ARDS). Acid-sensitive ion channel 1a (ASIC1a) is activated in acidic environments to regulate inflammatory process. However, the role of ASIC1a in ARDS is unclear. METHODS:In this study, we examined the expression of ASIC1a in airway epithelial cells in an acidic environment. We then investigated whether blocking ASIC1a could inhibit pyroptosis of airway epithelial cells and the molecular mechanism. In the mouse acute lung injury (ALI) model, we observed the changes of lung histopathology, arterial blood gas and pyroptosis related indexes after ASIC1a inhibition. Bronchoalveolar lavage fluid (BALF) from patients with ARDS were collected to explore the expression level of ASIC1a in ARDS patients. RESULTS:Inhibiting ASIC1a can reduce the airway epithelial cell pyroptosis induced by an extracellular acidic environment. ASIC1a can bind to PRKACA, and silencing ASIC1a and PRKACA can inhibit the occurrence of pyroptosis in airway epithelial cells. Compared with control group, arterial blood pH and PaO2 in ALI group were significantly reduced. The inflammation in the lungs is more intense, and the mRNA and protein of NLRP3, Caspase1 and GSDMD were increased, while ASIC1a specific blocker psalmotoxin-1 alleviated this phenomenon. The expression of ASIC1a in BALF of ARDS patients was significantly increased, especially in non-survival group. CONCLUSION:Acidic micro-environment can induce the increased expression of ASIC1a, and inhibition of ASIC1a can alleviate the inflammation and airway epithelial cell pyroptosis in ARDS. ASIC1a may be a new target for the treatment of ARDS.

Background Since December 2022, the Omicron variant has led to a widespread pandemic in China. The study was to explore the safety and effectiveness of Paxlovid for the treatment of coronavirus disease 2019 (COVID-19). Research design and methods We included patients at risk of developing severe COVID-19, all of whom exhibited mild to moderate symptoms and were admitted to three hospital centers. Patients were divided into two groups: one received Paxlovid alongside standard care, while the other was given only standard care. We compared clinical characteristics, hospital stay duration, and clinical outcomes between two groups. Multi-factor analysis determined the independent risk factors influencing the duration of hospitalization and disease progression. Results In the study, those treated with Paxlovid shorter hospital stays than those in the control group (p < 0.001). Multivariate analysis indicated that the absence of Paxlovid treatment was a distinct risk factor for hospitalizations lasting over 7 days (OR: 4.983, 95% CI: 3.828-6.486, p < 0.001) and 14 days (OR: 2.940, 95% CI: 2.402-3.597, p < 0.001). Conclusion Amid the Omicron outbreak, Paxlovid has proven to be a safe and effective treatment for reducing hospitalization durations for patients with mild to moderate COVID-19.

Dear Editor, Small cell lung cancer (SCLC) is notorious because of its rapid development, characterized by swift growth, high invasiveness, and limited treatment options.1, 2 Clinical trials have established the significant impact of integrating programmed cell death protein 1 (PD-1) axis interdict with traditional platinum-based chemotherapeutics for SCLC. This combination has been shown to enhance sustained overall survival, thereby setting a new standard for first-line therapy in SCLC.3, 4 In 2022, Serplulimab, approved in China, is the sole PD-1 inhibitor for extensive-stage SCLC.5, 6 Therefore, our study aims to develop a novel model utilizing machine learning and radiomic techniques to predict the therapeutic response to PD-1 inhibitors in SCLC patients. Note that, 233 SCLC patients were recruited for this study from three medical centres (Center I: n = 107; Center II: n = 54; Center III: n = 72), the specific process is depicted in Figure S1. Based on the RECIST evaluation criteria,7 the objective response rate was used to assess response to PD-1 inhibitors. The specific criteria are in Appendix 1. These SCLC patients were divided into the response cohort (n = 109) and the non-response cohort (n = 124). Table S1 provides a detailed overview of the clinical characteristics of these patients. Multivariate logistic regression analysis uncovered a potential association between neuron-specific enolase levels and the response of SCLC patients to PD-1 inhibitors (odds ratio [OR]:.995, 95% confidence interval [95% CI]:.992–.999; p = .019), as detailed in Table S2 and illustrated in Figure S2. From each region of interest analyzed using PyRadiomics,8 a total of 1,885 features were extracted. As described in Appendix 2, the feature selection process, which included a T-test and Least Absolute Shrinkage and Selection Operator regression analysis, enabled us to identify the five most critical radiomic features for the construction of our predictive model. This process is depicted in Figure 1. Details regarding these selected radiomic features, along with relevant information, are presented in Figure S3 and Table S3. Utilizing the previously identified radiomic features, we constructed a radiomics model within the training cohort employing the Light Gradient Boosting Machine method.9, 10 This model exhibited excellent predictive power, as evidenced by its performance in the training cohort, where it achieved an area under the curve (AUC) of.845 (95% CI = .776–.915). The model's robustness was further validated in two validation cohorts. In the internal validation cohort, the model achieved an AUC of.798 (95% CI = .637–.959), while in the external validation cohort, the AUC was.756 (95% CI = .644–.868). In contrast, the clinical model yielded varying AUC scores across the above three cohorts. Specifically, the AUCs were.842 (95% CI = .772–.911), 612 (95% CI = .403–.820) and.683 (95% CI = .559–.808). To enhance predictive accuracy, we constructed radiomics clinical nomograms for the three cohorts, integrating both radiomics and clinical data. These nomograms demonstrated superior predictive value, with AUC scores of.911 (95% CI = .860–.961) in the training,.818 (95% CI = .665–.970) in the internal validation, and.798 (95% CI = .694–.902) in the external validation. The receiver operating characteristic curves and the radiomics clinical conjoint nomograms are illustrated in Figure 2 for a more comprehensive understanding of the models' performance. The models' performance was rigorously assessed through calibration curves and decision curve analysis (DCA). These methods provided insight into the models' predictive accuracy and clinical utility. The results from this assessment revealed that the radiomic model was consistently better than the clinical model in terms of predictive value across all three cohorts. This underscores the enhanced effectiveness of incorporating radiomic features into predictive modelling for SCLC patient response to PD-1 inhibitors. Furthermore, the radiomics clinical nomograms, which integrate both radiomic and clinical data, demonstrated strong predictive capabilities in each of the three cohorts. This finding suggests their potential utility in guiding clinical decision-making. The calibration and DCA curves, which provide a visual representation of these findings, are displayed in Figure 3. These graphs offer a clear depiction of the models' calibration and their net benefits across different threshold probabilities. In addition to predictive value, the radiomic model also showed superior accuracy and sensitivity compared to the clinical model. Table 1 presents a comprehensive summary of various performance metrics, including accuracy, sensitivity, precision, recall, and F1 scores, for all three models across the three cohorts. This tabulated data provides an in-depth understanding of each model's performance and its implications for clinical application. Internal validation cohort This study successfully leveraged the synergy of radiomics and machine learning to create an innovative model for predicting the efficacy of PD-1 inhibitors in treating extensive-stage SCLC. The model showcased high accuracy and exemplary performance, reliably forecasting the response of SCLC patients to PD-1 inhibitor therapy. These findings underscore the model's potential as a valuable, non-invasive tool in guiding clinical decision-making and optimizing treatment strategies for SCLC. By offering insights into patient-specific responses to PD-1 inhibitors, this model represents a significant step forward in personalized cancer care, potentially improving treatment outcomes for individuals with extensive-stage SCLC. Thanks to the Radiology Department of the First Affiliated Hospital of Anhui Medical University for your help. The authors declare no conflict of interest. Young Jianghuai famous medical training project, Excellent physician Training program of Anhui Medical University, Research Fund project of Anhui Medical University (2023xkj144) and Research Fund of Anhui Institute of translational medicine (2023zhyx-C40). The study protocol underwent review and approval by the Institutional Review Committee of the First Affiliated Hospital of Anhui Medical University (Quick -PJ 2023-12-53), The First Affiliated Hospital of Soochow University ((2023) Batch No:371) and Dushu Lake Hospital of Soochow University (2023. Batch No:230133). The study was a multicenter retrospective study, and the Ethics Committee agreed to waive informed consent. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract Background COVID-19-associated pulmonary fibrosis remains frequent. This study aimed to investigate pulmonary redox balance in COVID-19 ARDS patients and possible relationship with pulmonary fibrosis and long-term lung abnormalities. Methods Baseline data, chest CT fibrosis scores, N-terminal peptide of alveolar collagen III (NT-PCP-III), transforming growth factor (TGF)-β1, superoxide dismutase (SOD), reduced glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) were first collected and compared between SARS-CoV-2 RNA positive patients with moderate to severe ARDS (n = 65, COVID-19 ARDS) and SARS-CoV-2 RNA negative non-ARDS patients requiring mechanical ventilation (n = 63, non-ARDS). Then, correlations between fibroproliferative (NT-PCP-III and TGF-β1) and redox markers were analyzed within COVID-19 ARDS group, and comparisons between survivor and non-survivor subgroups were performed. Finally, follow-up of COVID-19 ARDS survivors was performed to analyze the relationship between pulmonary abnormalities, fibroproliferative and redox markers 3 months after discharge. Results Compared with non-ARDS group, COVID-19 ARDS group had significantly elevated chest CT fibrosis scores (p < 0.001) and NT-PCP-III (p < 0.001), TGF-β1 (p < 0.001), GSSG (p < 0.001), and MDA (p < 0.001) concentrations on admission, while decreased SOD (p < 0.001) and GSH (p < 0.001) levels were observed in BALF. Both NT-PCP-III and TGF-β1 in BALF from COVID-19 ARDS group were directly correlated with GSSG (p < 0.001) and MDA (p < 0.001) and were inversely correlated with SOD (p < 0.001) and GSH (p < 0.001). Within COVID-19 ARDS group, non-survivors (n = 28) showed significant pulmonary fibroproliferation (p < 0.001) with more severe redox imbalance (p < 0.001) than survivors (n = 37). Furthermore, according to data from COVID-19 ARDS survivor follow-up (n = 37), radiographic residual pulmonary fibrosis and lung function impairment improved 3 months after discharge compared with discharge (p < 0.001) and were associated with early pulmonary fibroproliferation and redox imbalance (p < 0.01). Conclusions Pulmonary redox imbalance occurring early in COVID-19 ARDS patients drives fibroproliferative response and increases the risk of death. Long-term lung abnormalities post-COVID-19 are associated with early pulmonary fibroproliferation and redox imbalance. Graphical abstract