Search Results (181)

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) deposition driven by aberrant fibroblast-to-myofibroblast transition (FMT). However, the upstream regulators and downstream effectors of this process remain incompletely understood. Here, we identify acyl-CoA synthetase long-chain family member 4 (ACSL4), a lipid metabolic enzyme, as a critical mediator linking complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling to FMT via calcium signaling. In bleomycin (BLM)-induced pulmonary fibrosis of C57BL/6JGpt mice, and in C5a-stimulated primary lung fibroblasts, the expression of ACSL4 was markedly upregulated. Pharmacological inhibition of ACSL4 (PRGL493) or C5aR1 (PMX53) attenuated the deposition of ECM and suppressed the expression of fibrotic markers in vivo and in vitro. Mechanistically, the activation of C5a/C5aR1 signaling increased intracellular calcium levels and promoted the expression of ACSL4, while inhibition of calcium signaling (FK506) reversed the upregulation of ACSL4 and FMT-related changes, including the expression of α-smooth muscle actin (αSMA) and the migration of fibroblasts. Notably, inhibition of ACSL4 did not affect the proliferation of fibroblasts, suggesting its specific role in phenotypic transition. These findings demonstrate that ACSL4 functions downstream of C5a/C5aR1-induced calcium signaling to promote FMT and the progression of pulmonary fibrosis. Targeting ACSL4 may therefore offer a novel therapeutic strategy for IPF. Full article

Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial condition associated with significant systemic complications such as cardiovascular disease (CVD), metabolic disorders, muscle wasting, and sarcopenia. While Body Mass Index (BMI) is a well-established indicator of obesity and has prognostic value in COPD, its role in predicting disease outcomes is complex. Muscle wasting is prevalent in COPD patients and exacerbates disease severity, contributing to poor physical performance, reduced quality of life, and increased mortality. Additionally, COPD is linked to metabolic disorders, such as dyslipidemia and diabetes, which contribute to systemic inflammation and worse prognosis and, therefore, should be treated. The systemic inflammatory response plays a central role in the development of sarcopenia. In this review, we highlight the mixed efficacy of statins in managing dyslipidemia in COPD, considering side effects, including muscle toxicity in such a frail population. Alternative lipid-lowering therapies and nutraceuticals, in addition to standard treatment, have the potential to target hypercholesterolemia, which is a coexisting condition present in more than 50% of all COPD patients, without worsening muscle wasting. The interference between adipose tissue and lung, and particularly the potential protective role of adiponectin, an adipocytokine with anti-inflammatory properties, is also reviewed. Respiratory, metabolic and muscular health in COPD is comprehensively assessed. Identifying and managing dyslipidemia and paying attention to other relevant COPD comorbidities, such as sarcopenia and muscle wasting, is important to improve the quality of life and to reduce the clinical burden of COPD patients. Future research should focus on understanding the relationships between these intimate mechanisms to facilitate specific treatment for systemic involvement of COPD. Full article

The coronavirus disease 2019 (COVID-19) pandemic has led to substantial health and financial burdens worldwide, and vaccines provide hope for reducing the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWASs) may identify potential genetic factors involved in the development of COVID-19 breakthrough infections (BIs); however, very few or no GWASs have been conducted for COVID-19 BI thus far. We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BIs in a European population via the UK Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BIs and hospitalized infections. The polygenic risk score (PRS) and Hoeffding’s test were performed to reveal the genetic relationships between BIs and other medical conditions. Two independent loci (LD-clumped at r² = 0.01) reached genome-wide significance (p < 5 × 10⁻⁸), including rs36170929, which mapped to LOC102725191/VWDE, and rs28645263, which mapped to RETREG1. A pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. The PRS analyses revealed significant genetic overlap between COVID-19 BIs and heart failure and between HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BIs and asthma, lung abnormalities, schizophrenia, and type 1 diabetes on the basis of Hoeffding’s test. This GWAS revealed two significant loci that may be associated with COVID-19 BIs and a number of genes and pathways that may be involved in BIs. Genetic overlap with other diseases was identified. Further studies are warranted to replicate these findings and elucidate the mechanisms involved. Full article

Background: Mass spectrometry imaging (MSI) lipidomics is a subset of spatially resolved techniques wherein lipids are detected by mass spectrometry, allowing their multiplexed detection and acquiring position-correlated spectra along a tissue section. Rapid advances in the field provide solid evidence demonstrating how specific and regulated lipid distribution is in any biological context. Objectives: Herein, we describe the MSI, particularly matrix-assisted laser desorption/ionization (MALDI-MSI), challenges and advantages in defining human lung pathophysiology, particularly in lung cancer and chronic obstructive pulmonary disease, leading causes of death. Methods: MALDI-MSI analysis of lung tissue sections at 25 μm of lateral resolution allowed associating specific lipid profiles with the main tissues present and independently assessing the impact on lipid composition of smoking, chronic inflammation, and lung cancer. Results: Consistent with MALDI-MSI studies in tumor epithelia, arachidonic acid-containing phospholipids increased, agreeing with its role as a precursor of numerous bioactive molecules participating in cell differentiation and malignization. Next, a gene expression dataset of epithelial human non-small cell lung cancer samples was analyzed using system biology approaches, revealing that, consistent with the most relevant changes in lipid profiles, the network dominated by the tumor-associated module included genes tightly involved in phosphatidylinositol and sphingolipid metabolism. Hence, despite the intrinsic difficulties entailed by lung tissue handling, the results strongly encourage future analysis at higher lateral resolutions so that the lipidome changes associated with each lung cellular type, even subtype, could be fully mapped. Therefore, MALDI-MSI lipidomics definitively broadens the options, some still rather unexplored, to delve into pathophysiology at the cell-type level. Full article

Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects. Full article

Cardiovascular disease and cancer are major global causes of mortality. Dysfunctional lipid metabolism causes atherosclerosis, a driving force in arterial disease leading to heart attacks and strokes. In this review, we focus on emerging evidence for links between atherosclerosis and cancer. In atherosclerosis, modified and oxidized lipid particles promote plaque initiation and progression, with wider effects on cell and tissue responses. Oxidized and modified lipid particles bind to scavenger receptors (SRs) and promote intracellular signaling and pro-inflammatory responses. Increasing evidence points to SR-mediated activation and signaling promoting cancer cell growth and spread. In particular, the lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor activates NF-κB-regulated signal transduction pathways which modulate different cellular responses. LOX-1-regulated signaling events are implicated in both atherosclerosis and cancer, depending on the cell type. LOX-1 signaling modulates cell proliferation, epithelial–mesenchymal transition, neutrophil recruitment and apoptosis. Elevated LOX-1 levels are linked to poor prognosis in arterial disease and prostate, colorectal and lung cancers. Inhibition of LOX-1 function could thus provide new therapeutic strategies for targeting both atherosclerosis and cancer. Full article

Lipids play important roles in maintaining pulmonary structure, performing physiological functions and controlling the immune status of the lung. There is increasing evidence that lipid metabolism and immune activity are closely linked and that dysfunction in lipid metabolism contributes to the development and progression of chronic respiratory diseases such as COPD and asthma. These diseases are characterized by metabolic and immune dysregulation, with lipid mediators playing a key role in both the development and resolution of inflammation. In this regard, lipid metabolic pathways are attracting increasing attention as promising targets for biomarker detection and therapeutic intervention. Full article

Breast cancer metastasis remains the primary driver of patient mortality, involving dynamic interactions between tumor cells and distant organ microenvironments. In recent years, tumor cell-derived extracellular vesicles (EVs) have emerged as critical information carriers, playing central roles in breast cancer metastasis by mediating organ-specific pre-metastatic niche formation, immune modulation, and tumor cell adaptive evolution. Studies have demonstrated that EVs drive the metastatic cascade through the delivery of bioactive components, including nucleic acids (e.g., miRNAs, circRNAs), proteins (e.g., integrins, metabolic enzymes), and lipids, which collectively regulate osteoclast activation, immune cell polarization, vascular permeability alterations, and extracellular matrix (ECM) remodeling in target organs such as bone, the lungs, and the liver. Molecular heterogeneity in EVs derived from different breast cancer subtypes strongly correlates with organotropism, providing potential biomarkers for metastasis prediction. Leveraging the organotrophic mechanisms of EVs and their dual regulatory roles in metastasis (pro-metastatic and anti-metastatic), strategies targeting EV biogenesis, cargo loading, or delivery exhibits translational potential in diagnostics and therapeutics. In this review, we summarize recent advances in understanding the role of breast cancer-derived exosomes in mediating metastatic organotropism and discuss the potential clinical applications of targeting exosomes as novel diagnostic and therapeutic strategies for breast cancer. Full article

Ambient ozone (O₃) pollution, which has become a global problem, is associated with damage to various biological systems, as determined by many studies. However, there is limited experimental evidence regarding the systemic damage induced by O₃ exposure, and there are few associated studies on mice. In the present investigation, we constructed a subacute C57BL/6J female mouse model involving exposure to 0, 0.5, 1, or 2 ppm O₃ for 28 days (3 h/day). Body weights, pulmonary function, hematology, serum biochemistry, inflammatory factors, and injuries to various organs were assessed for O₃-exposed mice. After O₃ exposure, especially to 2 ppm O₃, mice showed a loss of body weight, abnormal glucose and lipid metabolism, respiratory and nervous system injuries, an inflammatory response, and pathological changes, which supported the data reported for epidemiology studies. In addition, the IL-6 levels in bronchoalveolar lavage fluid (BALF), the lungs, the livers, the kidneys, and the brains were increased, which indicated that IL-6 was associated with the damage to various organs induced by O₃ exposure. The present report highlights the pathological injury to various organs and provides a basis for further studies of the molecular mechanisms associated with O₃ exposure. Full article

The mortality risk in systemic sclerosis (SSc) is primarily determined by pulmonary involvement (interstitial lung disease (ILD), pulmonary fibrosis), pulmonary arterial hypertension (PAH), and cardiac involvement. With timely and intensive treatment, the disease can be halted or even improved. Therefore, early diagnosis remains crucial. Unfortunately, biomarkers currently available cannot meet this requirement. SSc is characterized by autoimmune inflammation, vasculopathy, and fibrosis. The immunometabolic characterization of autoimmune diseases contributes to a better understanding of the underlying inflammatory processes. In this narrative review, we included 13 studies on metabolomic patterns in SSc in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA). Current studies indicate an altered metabolome in SSc. All documented significant differences between patients with SSc and healthy controls, although the observed metabolomic patterns in SSc were inconsistent between studies. Metabolome alterations include, in particular, energy-related metabolic pathways such as glycolysis/gluconeogenesis, including the synthesis and degradation of ketones, fatty acid oxidation, amino acid-related metabolic pathways, lipid metabolism, and the tricarboxylic acid (TCA) cycle, including pyruvate metabolism. The most frequently examined organ complications with reported significant aberrations of the metabolome were skin involvement, ILD, and PAH. Conclusion: The detailed characterization of the SSc-specific metabolome promises a more comprehensive understanding of the pathogenic mechanisms of the disease. Furthermore, the detection of associations between specific metabolic aberrations and disease phenotypes bears hope for new biomarkers and an improved personalized approach to diagnostics, therapy, and follow-up in the management of SSc. Full article

The global prevalence of asthma is approximately 4.3%, and current asthma treatments focus on reducing symptoms, maintaining normal activity levels, and preventing the deterioration of lung function, rather than achieving a cure or complete prevention. We identified isochlorogenic acid C (ICGAC) as a potential natural medicine for the treatment of asthma. However, the bioavailability of ICGAC was low, ranging from 14.4% to 16.9%, suggesting the involvement of the gut microbiota. The full spectrum of ICGAC’s anti-asthmatic mechanism remains to be elucidated. This study investigated the mechanism by which ICGAC alleviates allergic asthma through the gut–lung axis. We discovered anti-asthma pathways and targets based on the selective regulation of lipid peroxidation and employed pharmacological tools to preliminarily validate their mechanisms and efficacy. To study the role of ICGAC in regulating the gut microbiota, we performed 16S rRNA gene sequencing and metabolite analysis. Furthermore, by combining molecular biology and lipid metabolomics, we elucidated the underlying anti-asthma mechanisms of ICGAC. The effective form of ICGAC varies between single and long-term administration. The oral administration of ICGAC enhances the gut-microbiota-derived production of short-chain fatty acids (SCFAs) as the active substances, modulates immune cell activity, influences the differentiation of T- and B-cells, and reduces airway inflammation. ICGAC also regulates the metabolic network of lipid mediators (LMs) and polyunsaturated fatty acids (PUFAs), thus exerting anti-inflammatory effects by modulating arachidonate lipoxygenase (ALOX) activity and LM levels. In addition, ICGAC enhanced the antioxidant response by upregulating the expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and nuclear factor erythroid 2-related factor 2 (Nrf2), while inhibiting the release of interleukin-4 (IL-4), thereby suppressing asthma inflammation and IgE production. The anti-asthmatic mechanism of oral ICGAC involves the inhibition of lipid peroxidation by chlorogenic acid (CGA) and SCFAs produced by the gut microbiota. ICGAC suppresses asthma-associated inflammatory and oxidative stress responses through the upregulation of GPX4, SLC7A11, and Nrf2 in lung tissue. This study not only provides a solid foundation for the potential clinical use of ICGAC in asthma treatment but also offers novel insights for future research and therapeutic strategies targeting asthma. Full article

Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention as a cancer treatment due to its ability to generate reactive oxygen and nitrogen species (RONS), inducing oxidative stress that damages cancer cells. This study aimed to investigate the combined effect of NBP and p-CA on the induction of ferroptosis in lung adenocarcinoma via the GPX4, xCT, and NRF2 pathways. H460 and A549 lung adenocarcinoma cells as well as normal lung cells (MRC5) were treated with p-CA, NBP, and their combination. Cell movement, intracellular RONS levels, and lipid peroxidation, along with apoptosis and ferroptosis-related gene expression, were evaluated by co-treatment. Co-treatment also significantly elevated NO₂⁻, NO₃⁻, and H₂O₂ levels and reduced cancer cell (H460, A549) viability (26, 31%) without affecting normal cells MRC5 (7%). Elevated MDA levels and changed expression of ferroptotic proteins indicated mitochondrial dysfunction, oxidative damage, lipid peroxidation, and DNA damage, which resulted in the induction of ferroptosis. These findings reveal a novel ferroptosis mechanism, emphasizing co-treatment for delivering bioavailable natural anticancer drugs. Full article

Background: Sepsis-induced acute lung injury (SALI) is a critical clinical challenge with high mortality. Metabolic dysregulation drives SALI pathogenesis, disrupting lung function and energy metabolism. Despite proven benefits, metabolic restoration is underused in sepsis. This study explores chiglitazar’s role in balancing metabolism to protect against SALI. Methods: The protective effects of chiglitazar in CLP rats were demonstrated by the survival curve, histological analysis, and immunohistochemical analysis in the lung tissue. Metabolomic and lipidomic analyses of lung tissue samples using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) were performed to evaluate metabolic shifts induced by CLP surgery and chiglitazar pretreatment. The mRNA and protein levels of the underlying targets directing nicotinamide adenine dinucleotide (NAD+) and triglyceride synthesis were analyzed by qPCR and Western blotting. To validate the mechanism by which chiglitazar protected against SALI, the SIRT1 inhibitor EX-527 was applied to human normal lung epithelial (BEAS-2B) cells and another batch of rats to observe its reverse effect against chiglitazar’s action. Results: Chiglitazar pretreatment significantly restored NAD+ and improved dysregulated lipid metabolism by enhancing the synthesis of triglycerides (TGs) and suppressing accumulated fatty acids (FAs). The metabolic modulation mediated by chiglitazar was associated with the upregulations of the SIRT1/PGC-1α/PPARα/GPAT3 axis. Co-treatment with EX-527 in LPS-stimulated BEAS-2B cells and CLP rats inhibited the effects of chiglitazar on the aforementioned signaling pathways and worsened the protective effects of chiglitazar on lung injury, respectively. Conclusions: Chiglitazar alleviates SALI by restoring NAD+ and TG synthesis, highlighting the balancing of metabolism as a promising therapeutic strategy in the management of SALI. Full article

It has been reported that miR-375-3p plays a critical role in numerous diseases. To elucidate its biological function, particularly its differential expression and specific mechanisms of action in Alzheimer’s disease (AD) and small cell lung cancer (SCLC), this study comprehensively explores the associations between the target genes of miR-375-3p and both AD and SCLC. The focus is specifically on its impact on disease progression and the remodeling of the tumor microenvironment. We utilized databases such as the miRNA TargetScanHuman 8.0 database and the STRING database, to construct a protein–protein interaction (PPI) network for the classification and discrimination of the miR-375-3p gene, resulting in the identification of 14 intersecting target genes. Subsequently, two key genes, ASCL1 and CHD7, along with their associated genes, were further analyzed using Spearman correlation analysis. The identified key genes were then subjected to GO function annotation and KEGG pathway enrichment analysis. It was determined that pathways related to lipid metabolism, autophagy, and cell apoptosis were differentially expressed in the AD and SCLC environments, with nine related pathways identified, among which the PI3K pathway was the most prominent. Finally, we demonstrated that the expression of miR-375-3p significantly differed between the two environments, with higher expression levels observed in AD compared to SCLC. Our study confirmed that miR-375-3p can promote apoptosis, regulate lipid metabolism, influence the progression of neurodegenerative diseases, and inhibit the proliferation and metastasis of tumor cells. These research findings may have significant implications for the future treatment of AD and SCLC. Full article

The role of claudin-17 (Cldn17), a tight-junction protein, in vascular permeability remains unclear. We investigated the impact of Cldn17 suppression on vascular permeability. The Miles assay demonstrated significantly increased vascular permeability in the lungs and skin of Cldn17^−/− mice, as evidenced by elevated Evan’s blue dye extravasation. The Matrigel plug assay demonstrated increased hemoglobin extravasation. Histopathological analysis revealed alveolar flooding, inflammatory cell infiltration, and lung injury in Cldn17^−/− lungs. Wet/dry lung weight ratios indicated pulmonary edema, supporting the role of Cldn17 in pulmonary fluid balance, which was exacerbated with lipopolysaccharide administration. Ribosomal nucleic acid sequencing identified distinct transcriptional changes, with the principal component analysis showing clear clustering. Differential gene expression analysis highlighted significant alterations in inflammatory and metabolic pathways. Gene ontology and pathway enrichment analyses revealed the upregulation of immune-related processes, including leukocyte adhesion, interferon–gamma response, and neutrophil degranulation, alongside metabolic dysregulation affecting lipid transport and cytoskeletal organization. Reactome pathway analysis implicated Cldn17 in antigen presentation, interleukin-17 signaling, and inflammatory responses. These findings establish Cldn17 as a critical regulator of vascular permeability and immune homeostasis. Its deficiency drives vascular leakage, exacerbates lung injury, and alters immune signaling pathways, underscoring its potential as a therapeutic target for inflammatory lung diseases. Full article