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Lymphangioleiomyomatosis (LAM) is a rare progressive disease that affects women of reproductive age and is characterized by cystic lung destruction, airflow obstruction, and lymphatic dysfunction. Current diagnostic methods are costly or lack sufficient specificity, highlighting the need for novel non-invasive approaches. Exhaled breath analysis using real-time proton mass spectrometry (PTR-MS) presents a promising strategy for identifying disease-specific volatile organic compounds (VOCs). This cross-sectional study analyzed exhaled breath samples from 51 LAM patients and 51 age- and sex-matched healthy controls. PTR-time-of-flight mass spectrometry (PTR-TOF-MS) was employed to identify VOC signatures associated with LAM. Data preprocessing, feature selection, and statistical analyses were performed using machine learning models, including gradient boosting classifiers (XGBoost), to identify predictive biomarkers of LAM and its complications. We identified several VOCs as potential biomarkers of LAM, including m/z = 90.06 (lactic acid) and m/z = 113.13. VOCs predictive of disease complications included m/z = 49.00 (methanethiol), m/z = 48.04 (O-methylhydroxylamine), and m/z = 129.07, which correlated with pneumothorax, obstructive ventilation disorders, and radiological findings of lung cysts and bronchial narrowing. The classifier incorporating these biomarkers demonstrated high diagnostic accuracy (AUC = 0.922). This study provides the first evidence that exhaled breath VOC profiling can serve as a non-invasive additional tool for diagnosing LAM and predicting its complications. These findings warrant further validation in larger cohorts to refine biomarker specificity and explore their clinical applications in disease monitoring and personalized treatment strategies.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are prevalent obstructive lung diseases with distinct inflammatory pathways but overlapping clinical features. Bronchodilator responsiveness (BDR) is a key diagnostic criterion, yet its metabolic determinants are poorly understood. Objective: This cross-sectional study investigated whether integrated profiling of exhaled volatile organic compounds (VOCs) and clinical biomarkers can differentiate BA, COPD, and health, and predict BDR. Methods: Exhaled breath from 160 BA patients, 128 COPD patients, and 254 healthy controls was analyzed in real-time using proton-transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) during tidal and forced expiration. Clinical assessment included spirometry, fractional exhaled nitric oxide (FeNO), blood eosinophil count, and total IgE. Machine-learning (XGBoost) was employed for feature selection and model development. Results: Distinct VOC signatures effectively discriminated disease groups from controls and from each other. The model for distinguishing asthma from healthy controls achieved an AUC of 0.747 during normal quiet breathing and 0.710 during forced exhale. For discriminating COPD from healthy controls, the model performance was higher, with an AUC of 0.821 for normal quiet breathing and 0.856 for forced exhale. A model integrating VOC profiles with clinical biomarkers (FeNO, eosinophils, IgE) demonstrated very high accuracy in internal validation in predicting BDR (AUC = 1.000 for tidal breathing; AUC = 0.970 for forced expiration). Specific mass spectral features (m/z 79, m/z 101) were significantly associated with a positive BDR test. Conclusions: This study delineates disease-specific VOC signatures and underscores the profound synergy between exhaled metabolomics and clinical immunology for identifying associations treatment response, advocating for the integration of real-time breath analysis into personalized management strategies for obstructive lung diseases.

Background/Aims: Endothelial-mesenchymal transition (EndMT) has been shown to take part in the generation and progression of diverse diseases, involving a series of changes leading to a loss of their endothelial characteristics and an acquirement of properties typical of mesenchymal cells. Low-intensity pulsed ultrasound (LIPUS) is a new therapeutic option that has been successfully used in fracture healing. However, whether LIPUS can inhibit oxidative stress-induced endothelial cell damages through inhibiting EndMT remained unknown. This study aimed to investigate the protective effects of LIPUS against oxidative stress-induced endothelial cell damages and the underlying mechanisms. Methods: EndMT was induced by H 2 O 2 (100 µm for seven days). Human aortic endothelial cells (HAECs) were exposed to H 2 O 2 with or without LIPUS treatment for seven days. The expression of EndMT markers (CD31, VE-cadherin, FSP1 and α-SMA) were analyzed. The levels of total and phosphorylated PI3K and AKT proteins were detected by Western Blot analysis. Cell chemotaxis was determined by wound healing and transwell assay. Results: LIPUS relieved EndMT by decreasing ROS accumulation and increasing activation of the PI3K signaling cascade. LIPUS alleviated the migration of EndMT-derived mesenchymal-like cells through reducing extracellular matrix (ECM) deposition that is associated with matrix metallopeptidase (MMP) proteolytic activity and collagen production. Conclusion: LIPUS produces cytoprotective effects against oxidative injuries to endothelial cells through suppressing the oxidative stress-induced EndMT, activating the PI3K/AKT pathway under oxidative stress, and limiting cell migration and excessive ECM deposition.

Emerging evidence has suggested the critical role of endothelial to mesenchymal transition (EndMT) in fibrotic diseases. The present study was designed to examine whether EndMT is involved in arsenic trioxide (As 2 O 3 )-induced cardiac fibrosis and to explore the underlying mechanisms. Cardiac dysfunction was observed in rats after exposure to As 2 O 3 for 15 days using echocardiography and the deposition of collagen was detected by Masson’s trichrome staining and electron microscope. EndMT was indicated by the loss of endothelial cell markers (VE-cadherin and CD31) and the acquisition of mesenchymal cell markers (α-SMA and FSP1) determined by RT-PCR at the mRNA level and Western blot and immunofluorescence analysis at the protein level. In the in-vitro experiments, endothelial cells acquired a spindle-shaped morphology accompanying downregulation of the endothelial cell markers and upregulation of the mesenchymal cell markers when exposed to As 2 O 3 . As 2 O 3 activated the AKT/GSK-3β/Snail signaling pathway and blocking this pathway with PI3K inhibitor (LY294002) abolished EndMT in As 2 O 3 -treated endothelial cells. Our results highlight that As 2 O 3 is an EndMT-promoting factor during cardiac fibrosis, suggesting that targeting EndMT is beneficial for preventing As 2 O 3 -induced cardiac toxicity.

Haemodynamic indices are widely used in clinical practice when deciding on a particular type of treatment. Low quality of the computed tomography data and tachycardia complicate interpretation of the measured or simulated values. In this work, we present a novel approach for evaluating resistances in terminal coronary arteries. Using 14 measurements from 10 patients, we show that this algorithm retains the accuracy of 1D haemodynamic simulations in less detailed (truncated) geometric models of coronary networks. We also apply the variable systole fraction model to study the effect of elevated heart rate on the values of fractional flow reserve (FFR), coronary flow reserve (CFR) and instantaneous wave-free ratio (iFR). We conclude that tachycardia may produce both overestimation or underestimation of coronary stenosis significance.

: Nicotine exposure via cigarette smoking is strongly associated with atherosclerosis. However, the underlying mechanisms remain poorly understood. The current study aimed to identify whether endothelial to mesenchymal transition (EndMT) contributes to nicotine-induced atherosclerosis. : ApoE mice were administered nicotine in their drinking water for 12 weeks. The effects of nicotine on EndMT were determined by immunostaining on aortic root and RNA analysis in aortic intima. nicotine-treated cell model was established on human aortic endothelial cells (HAECs). The effects of nicotine on the expression of EndMT-related markers, ERK1/2 and Snail were quantified by real-time PCR, western blot and immunofluorescent staining. : Nicotine treatment resulted in larger atherosclerotic plaques in ApoE mice. The vascular endothelial cells from nicotine-treated mice showed mesenchymal phenotype, indicating EndMT. Moreover, nicotine-induced EndMT process was accompanied by cytoskeleton reorganization and impaired barrier function. The α7 nicotine acetylcholine receptor (α7nAChR) was highly expressed in HAECs and its antagonist could effectively relieve nicotine-induced EndMT and atherosclerotic lesions in mice. Further experiments revealed that ERK1/2 signaling was activated by nicotine, which led to the upregulation of Snail. Blocking ERK1/2 with inhibitor or silencing Snail by small interfering RNA efficiently preserved endothelial phenotype upon nicotine stimulation. : Our study provides evidence that EndMT contributes to the pro-atherosclerotic property of nicotine. Nicotine induces EndMT through α7nAChR-ERK1/2-Snail signaling in endothelial cells. EndMT may be a therapeutic target for smoking-related endothelial dysfunction and cardiovascular disease.

Background: Atherosclerosis and its associated chronic inflammation of the arterial wall disrupt fatty acid metabolism, leading to changes in plasma fatty acid composition. These alterations can be used to improve disease diagnosis and risk stratification by the development and application of specific lipidomic indices. Objectives: The objectives of this study are to evaluate the performance of conventional fatty acid indices and enhance diagnostic efficiency in atherosclerosis by introducing novel index based on plasma PUFA n-6 and n-3 content (Omega-6/3 Balance Index, O6/3-BI), as well as the perspective SFA/MUFA ratio (stearic/oleic acid ratio, C18:0/C18:1n-9) and a logit function combining PUFA and SFA/MUFA biomarkers. Methods: Plasma fatty acids were quantified by LC-MS/MS in healthy controls (n = 50) and patients with carotid atherosclerosis (n = 52), stratified by atorvastatin, rosuvastatin, or no statin therapy. The conventional indices (the Omega-3 Status (EPA + DHA), AA/EPA, and the omega-6/omega-3 ratio), and pathway ratios (C18:0/C18:1n-9; and C20:4n-6/C22:4n-6), as well as the newly introduced PUFA index and combined PUFA-SFA/MUFA logit function, were calculated. Their diagnostic performance for distinguishing atherosclerosis was assessed by a receiver operating characteristic (ROC) analysis with the cross-validation and calculation of Cliff’s Δ effect size. Results: The conventional parameters demonstrated a poor to low discrimination ability of the atherosclerosis patients’ groups from healthy controls (area under the ROC curve, AUC 0.548–0.711). In statin-treated patients, these conventional markers lost significance. The newly introduced PUFA index and SFA/MUFA ratio demonstrated improved patients’ discrimination with AUC 0.734–0.780 for the former and strong predictive power with AUC 0.831–0.858 for the latter marker and maintained their diagnostic value under statin therapy. The most significant positive effect size was observed for the SFA/MUFA ratio with Cliff’s Δ = 0.67–0.71. The combined PUFA-SFA/MUFA logit function also demonstrated a strong predictive power with AUC = 0.880 (Cliff’s Δ = −0.76), outperforming any single index. Conclusions: The newly introduced lipidomic index based on the PUFA content, SFA/MUFA ratio, and a logit function combining PUFA-SFA/MUFA biomarkers demonstrated a substantially better discrimination of atherosclerosis-related fatty acid metabolic disturbances than conventional fatty acid biomarkers.

Background Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. Methods Apolipoprotein E deficiency ( ApoE −/− ) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA–protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. Results The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. Conclusion These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Coronary artery disease (CAD) is one of the main causes of death in the world. Functional indices such as fractional flow reserve (FFR), coronary flow reserve (CFR) and instantaneous wave-free ratio (iFR) are used to estimate the severity of CAD. Approximately 30–50% of patients have residual myocardial ischaemia even after formally successful percutaneous coronary intervention (PCI). Myocardial perfusion impairment is one of the main factors responsible for recurrence. We propose a novel 1D model of coronary hemodynamics that takes into account myocardial contraction, stenoses and impaired microcirculation. It uses non-invasively acquired data. The model is able to simulate FFR and iFR with a mean relative error of 3% and a standard mean deviation of 0.04. We find that healthy FFR and iFR values in the short and long term do not always correspond to healthy CFR values and recovery of coronary blood flow. We also show that PCI of stenosis also improves hemodynamic indices in adjacent stenosed vessels, with a more pronounced effect in the long term.

Background/Objectives: Omega-3 highly unsaturated fatty acids (HUFAs), particularly EPA and DHA, have anti-inflammatory and lipid-modulating properties for treating atherosclerosis. However, the relationship between plasma fatty acid profiles, omega-3 status, and statin efficacy in carotid atherosclerosis remains poorly defined. Objectives: This study evaluates plasma and plaque fatty acid (FA) composition, explores their associations with plaque stability, and examines the relationship of omega-3 levels, lipid biomarkers (VLDL-C, LDL-C, HDL-C, total cholesterol, and triglycerides) with statin and β-blocker treatment. A mathematical model was developed to predict the erythrocyte omega-3 index from plasma. Methods: In this case–control study, plasma and carotid plaques of 52 patients undergoing carotid endarterectomy were analyzed. Plasma was compared with that of 50 healthy controls. FAs were quantified by LC-MS/MS. Plaques were histologically classified as stable or unstable. Results: Atherosclerotic patients showed disturbed FA metabolism, including decreased plasma omega-3 EPA + DHA, SFAs and HUFAs, increased MUFAs, and impaired desaturase and elongase activity. Unstable plaques had higher MUFA and lower HUFA content compared with stable plaques. Significant correlations between plasma EPA + DHA and HDL-C and triglycerides were observed in statin-naïve patients, whereas statins appeared to attenuate these associations. Co-treatment with β-blockers had no significant effect. A validated logit-based model accurately predicted the erythrocyte omega-3 index from plasma (R2 = 0.782). Conclusions: Altered plasma and plaque FA profiles correlate with atherosclerosis’s plaque instability and inflammatory lipid profiles. Statins significantly influence these associations, suggesting their complex interaction with lipid metabolism. Plasma measurements of omega-3 fatty acids in combination with predictive modelling may be beneficial for diagnostic and therapeutic monitoring in carotid atherosclerosis.