Exosomal MicroRNAs: An Emerging Important Regulator in Acute Lung Injury.

Acute lung injury (ALI) is a clinically life-threatening form of respiratory failure with a mortality of 30%-40%. Acute respiratory distress syndrome is the aggravated form of ALI. Exosomes are extracellular lipid vesicles ubiquitous in human biofluids with a diameter of 30-150 nm. They can serve as carriers to convey their internal cargo, particularly microRNA (miRNA), to the target cells involved in cellular communication. In disease states, the quantities of exosomes and the cargo generated by cells are altered. These exosomes subsequently function as autocrine or paracrine signals to nearby or distant cells, regulating various pathogenic processes. Moreover, exosomal miRNAs from multiple stem cells can provide therapeutic value for ALI by regulating different signaling pathways. In addition, changes in exosomal miRNAs of biofluids can serve as biomarkers for the early diagnosis of ALI. This study aimed to review the role of exosomal miRNAs produced by different sources participating in various pathological processes of ALI and explore their potential significance in the treatment and diagnosis.

Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction.

Qingyi decoction (QYD) has anti-inflammatory pharmacological properties and substantial therapeutic benefits on severe acute pancreatitis (SAP) in clinical practice. However, its protective mechanism against SAP-associated acute lung injury (ALI) remains unclear. In this study, we screened the active ingredients of QYD from the perspective of network pharmacology to identify its core targets and signaling pathways against SAP-associated ALI. Rescue experiments were used to determine the relationship between QYD and ferroptosis. Then, metabolomics and 16s rDNA sequencing were used to identify differential metabolites and microbes in lung tissue. Correlation analysis was utilized to explore the relationship between core targets, signaling pathways, metabolic phenotypes, and microbial flora, sorting out the potential molecular network of QYD against SAP-associated lung ALI. Inflammatory damage was caused by SAP in the rat lung. QYD could effectively alleviate lung injury, improve respiratory function, and significantly reduce serum inflammatory factor levels in SAP rats. Network pharmacology and molecular docking identified three key targets: ALDH2, AnxA1, and ICAM-1. Mechanistically, QYD may inhibit ferroptosis by promoting the ALDH2 expression and suppress neutrophil infiltration by blocking the cleavage of intact AnxA1 and downregulating ICAM-1 expression. Ferroptosis activator counteracts the pulmonary protective effect of QYD in SAP rats. In addition, seven significant differential metabolites were identified in lung tissues. QYD relatively improved the lung microbiome's abundance in SAP rats. Further correlation analysis determined the correlation between ferroptosis, differential metabolites, and differential microbes. In this work, the network pharmacology, metabolomics, and 16s rDNA sequencing were integrated to uncover the mechanism of QYD against SAP-associated ALI. This novel integrated method may play an important role in future research on traditional Chinese medicine.

Fighting Fire with Fire: Exosomes and Acute Pancreatitis-Associated Acute Lung Injury.

Acute pancreatitis (AP) is a prevalent clinical condition of the digestive system, with a growing frequency each year. Approximately 20% of patients suffer from severe acute pancreatitis (SAP) with local consequences and multi-organ failure, putting a significant strain on patients' health insurance. According to reports, the lungs are particularly susceptible to SAP. Acute respiratory distress syndrome, a severe type of acute lung injury (ALI), is the primary cause of mortality among AP patients. Controlling the mortality associated with SAP requires an understanding of the etiology of AP-associated ALI, the discovery of biomarkers for the early detection of ALI, and the identification of potentially effective drug treatments. Exosomes are a class of extracellular vesicles with a diameter of 30-150 nm that are actively released into tissue fluids to mediate biological functions. Exosomes are laden with bioactive cargo, such as lipids, proteins, DNA, and RNA. During the initial stages of AP, acinar cell-derived exosomes suppress forkhead box protein O1 expression, resulting in M1 macrophage polarization. Similarly, macrophage-derived exosomes activate inflammatory pathways within endothelium or epithelial cells, promoting an inflammatory cascade response. On the other hand, a part of exosome cargo performs tissue repair and anti-inflammatory actions and inhibits the cytokine storm during AP. Other reviews have detailed the function of exosomes in the development of AP, chronic pancreatitis, and autoimmune pancreatitis. The discoveries involving exosomes at the intersection of AP and acute lung injury (ALI) are reviewed here. Furthermore, we discuss the therapeutic potential of exosomes in AP and associated ALI. With the continuous improvement of technological tools, the research on exosomes has gradually shifted from basic to clinical applications. Several exosome-specific non-coding RNAs and proteins can be used as novel molecular markers to assist in the diagnosis and prognosis of AP and associated ALI.

[Research progress on molecular mechanism of transcription factor C/EBPß in lung diseases].

CCAAT enhancer binding protein ß (C/EBPß), as a nuclear transcription factor necessary for the development of liver, airway epithelium, and adipose tissue, plays a vital role in physiological processes related to cell proliferation, apoptosis, and differentiation. However, the up-regulation of C/EBPß activates signal pathways related to inflammatory response, epithelial-mesenchymal transition, cell proliferation and invasion, immune response, and angiogenesis by regulating a series of downstream genes transcription promotes the development of lung diseases. Therefore, targeting C/EBPß may be a potential treatment strategy for lung diseases. This paper summarizes the regulatory effects of C/EBPß and related signaling pathways in lung infection, asthma, chronic obstructive pulmonary disease, lung injury, pulmonary fibrosis, and lung cancer to provide a theoretical basis for the precision medicine of lung diseases.

C/EBPß Promotes LPS-Induced IL-1ß Transcription and Secretion in Alveolar Macrophages via NOD2 Signaling.

Objective: C/EBPß, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPß in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPß in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPß. Methods: Rat AMs were infected with Lv-sh-C/EBPß and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1ß were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPß knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPß. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPß with the structure of helenalin as a reference. Results: Following stimulation with LPS, AMs exhibited an increased expression of C/EBPß. C/EBPß knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPß knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPß, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPß knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPß inhibitor) and demonstrate a great binding capacity to C/EBPß. Conclusion: Ablation of C/EBPß may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPß inhibitors.

Electrochemical oxidative C-H/N-H cross-coupling for C-N bond formation with hydrogen evolution.

Under metal catalyst-free and exogenous-oxidant-free conditions, a series of C-3 aminated imidazo[1,2-a]pyridines were synthesized by electrochemical intermolecular oxidative C-H/N-H cross-coupling. Furthermore, by using a catalytic amount of ferrocene as the mediator, electrochemical intramolecular oxidative C-H/N-H cross-coupling for the synthesis of 10H-benzo[4,5]imidazo[1,2-a]indole derivatives has also been accomplished.