Network pharmacology-based research into the mechanism of ferulic acid on acute lung injury through enhancing transepithelial sodium transport.

Ethnopharmacological Relevance: Ferulic acid (FA) has shown potential therapeutic applications in treating lung diseases. However, the underlying mechanisms by which FA ameliorates acute lung injury (ALI) have not been distinctly elucidated.

Aim Of The Study: The project aims to observe the therapeutic effects of FA on lipopolysaccharide-induced ALI and to elucidate its specific mechanisms in regulating epithelial sodium channel (ENaC), which majors in alveolar fluid clearance during ALI.

Mesenchymal stem cell conditioned medium alleviates acute lung injury through KGF-mediated regulation of epithelial sodium channels.

Acute lung injury (ALI) is a progressive inflammatory injury, and mesenchymal stem cells (MSCs) can be used to treat ALI. MSC-conditioned medium (MSC-CM) contains many cytokines, in which keratinocyte growth factor (KGF) is a soluble factor that plays a role in lung development. We aim to explore the protective effects of MSCs secreted KGF on ALI, and investigate the involvement of epithelial sodium channel (ENaC), which are important in alveolar fluid reabsorption.

Luteolin Enhances Transepithelial Sodium Transport in the Lung Alveolar Model: Integrating Network Pharmacology and Mechanism Study.

Luteolin (Lut), a natural flavonoid compound existing in (L.) Britton, has been proven to play a protective role in the following biological aspects: inflammatory, viral, oxidant, and tumor-related. Lut can alleviate acute lung injury (ALI), manifested mainly by preventing the accumulation of inflammation-rich edematous fluid, while the protective actions of Lut on transepithelial ion transport in ALI were seldom researched.

Regulation of Epithelial Sodium Transport by SARS-CoV-2 Is Closely Related with Fibrinolytic System-Associated Proteins.

Dyspnea and progressive hypoxemia are the main clinical features of patients with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary pathology shows diffuse alveolar damage with edema, hemorrhage, and the deposition of fibrinogens in the alveolar space, which are consistent with the Berlin Acute Respiratory Distress Syndrome Criteria. The epithelial sodium channel (ENaC) is a key channel protein in alveolar ion transport and the rate-limiting step for pulmonary edema fluid clearance, the dysregulation of which is associated with acute lung injury/acute respiratory distress syndrome.

Ferulic Acid: A Review of Pharmacology, Toxicology, and Therapeutic Effects on Pulmonary Diseases.

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species and activate nuclear factor erythroid-2-related factor-2/heme oxygenase-1 signaling, exerting anti-oxidative effects. The anti-inflammatory effect of FA is mainly related to the p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways.

Fibrinolytic system and COVID-19: From an innovative view of epithelial ion transport.

Lifeways of worldwide people have changed dramatically amid the coronavirus disease 2019 (COVID-19) pandemic, and public health is at stake currently. In the early stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, fibrinolytic system is mostly inhibited, which is responsible for the development of hypofibrinolysis, promoting disseminated intravascular coagulation, hyaline membrane formation, and pulmonary edema. Whereas the common feature and risk factor at advanced stage is a large amount of fibrin degradation products, including D-dimer, the characteristic of hyperfibrinolysis.

Submersion and hypoxia inhibit alveolar epithelial Na transport through ERK/NF-κB signaling pathway.

Background: Hypoxia is associated with many respiratory diseases, partly due to the accumulation of edema fluid and mucus on the surface of alveolar epithelial cell (AEC), which forms oxygen delivery barriers and is responsible for the disruption of ion transport. Epithelial sodium channel (ENaC) on the apical side of AEC plays a crucial role to maintain the electrochemical gradient of Na and water reabsorption, thus becomes the key point for edema fluid removal under hypoxia. Here we sought to explore the effects of hypoxia on ENaC expression and the further mechanism related, which may provide a possible treatment strategy in edema related pulmonary diseases.

Competitive cleavage of SARS-CoV-2 spike protein and epithelial sodium channel by plasmin as a potential mechanism for COVID-19 infection.

Cleavage of the furin site in SARS-CoV-2 spike (S) protein accounts for increased transmissibility of COVID-19 by promoting the entry of virus into host cells through specific angiotensin-converting enzyme 2 (ACE2) receptors. Plasmin, a key serine protease of fibrinolysis system, cleaves the furin site of γ subunit of human epithelial sodium channels (ENaCs). Sharing the plasmin cleavage by viral S and host ENaC proteins may competitively inter-regulate SARS-CoV-2 transmissibility and edema resolution via the ENaC pathway.

Expression profiles of respiratory V-ATPase and calprotectin in SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a pandemic threat that has been declared a public health emergency of international concern, whereas the effects of cellular microenvironment in the pathogenesis of SARS-CoV-2 are poorly understood. The detailed message of intracellular/lysosome pH was rarely concerned in SARS-CoV-2 infection, which was crucial for the cleavage of SARS-CoV-2 spike (S) protein. Calprotectin, an endogenous danger signal to activate inflammatory response, was vital for the proceeding of COVID-19.

Effects of hypoxia on respiratory diseases: perspective view of epithelial ion transport.

The balance of gas exchange and lung ventilation is essential for the maintenance of body homeostasis. There are many ion channels and transporters in respiratory epithelial cells, including epithelial sodium channel, Na,K-ATPase, cystic fibrosis transmembrane conductance regulator, and some transporters. These ion channels/transporters maintain the capacity of liquid layer on the surface of respiratory epithelial cells and provide an immune barrier for the respiratory system to clear off foreign pathogens.

Mesenchymal Stem Cell Therapy for ALI/ARDS: Therapeutic Potential and Challenges.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical common disease caused by various pathological factors and can induce serious complications. There is still no specific and effective method for the treatment of ALI/ARDS. Mesenchymal stem cells (MSCs) have been one of the treatment methods for ALI, which can regulate related signal pathways such as PI3K/AKT, Wnt, and NF-κB to reduce inflammation.

MiR-199a-3p in mouse bone marrow mesenchymal stem cell exosomes increases epithelial sodium channel expression in lung injury.

Acute lung injury (ALI) causes significant morbidity and mortality in critically ill patients, which often presents with extensive accumulation of activated inflammatory cells and diffused alveolar damage accompanied by oxidative stress. Exosomes are nanovesicles, which have notable anti-inflammatory and repair properties, thus alleviating the symptoms of ALI. Epithelial sodium channel (ENaC) is essential for the transepithelial absorption of Na and fluid from alveolar spaces.

Small Extracellular Vesicles Containing miR-34c Derived from Bone Marrow Mesenchymal Stem Cells Regulates Epithelial Sodium Channel via Targeting MARCKS.

Epithelial sodium channel (ENaC) is a pivotal regulator of alveolar fluid clearance in the airway epithelium and plays a key role in the treatment of acute lung injury (ALI), which is mainly composed of the three homologous subunits (α, β and γ). The mechanisms of microRNAs in small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC-sEVs) on the regulation of lung ion transport are seldom reported. In this study, we aimed at investigating whether miR-34c had an effect on ENaC dysfunction induced by lipopolysaccharide and explored the underlying mechanism in this process.

MiR-130a-3p Alleviates Inflammatory and Fibrotic Phases of Pulmonary Fibrosis Through Proinflammatory Factor TNF-α and Profibrogenic Receptor TGF-βRII.

Pulmonary fibrosis (PF) is a progressive disease characterized by extracellular matrix (ECM) deposition that destroys the normal structure of the lung parenchyma, which is classified into two successive inflammatory and fibrotic phases. To investigate the anti-inflammatory and anti-fibrotic roles of miR-130a-3p in mice with bleomycin (BLM)-induced PF and the underlying mechanism, we performed single-cell RNA-sequencing analysis, which demonstrated that BLM increased/decreased the percentage of macrophages and fibroblasts/epithelial cells in PF lungs, respectively. The differentially expressed genes were enriched in PPAR signaling pathway and lysosome, ECM-receptor interaction and ribosome, and metabolism reaction.

Airway Basal Cells Mediate Hypoxia-Induced EMT by Increasing Ribosome Biogenesis.

Excessive secretion of airway mucus and fluid accumulation are the common features of many respiratory diseases, which, in turn, induce cell hypoxia in the airway epithelium, resulting in epithelial-mesenchymal transition (EMT) and ultimately fibrosis. However, the mechanisms of EMT induced by hypoxia in the airway are currently unclear. To mimic the status of edematous fluid retention in the airway, we cultured primary mouse tracheal epithelial cells (MTECs) in a liquid-liquid interface (LLI) mode after full differentiation in a classic air-liquid interface (ALI) culture system.

Ferulic acid ameliorates lipopolysaccharide-induced tracheal injury via cGMP/PKGII signaling pathway.

Background: Tracheal injury is a common clinical condition that still lacks an effective therapy at present. Stimulation of epithelial sodium channel (ENaC) increases Na transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects.

Bone marrow mesenchymal stem cell-conditioned medium facilitates fluid resolution via miR-214-activating epithelial sodium channels.

Acute lung injury (ALI) is featured with severe lung edema at the early exudative phase, resulting from the imbalance of alveolar fluid turnover and clearance. Mesenchymal stem cells (MSCs) belong to multipotent stem cells, which have shown potential therapeutic effects during ALI. Of note, MSC-conditioned medium (MSC-CM) improved alveolar fluid clearance (AFC) in vivo, whereas the involvement of miRNAs is seldom known.

Luteolin attenuates lipopolysaccharide-induced acute lung injury/acute respiratory distress syndrome by activating alveolar epithelial sodium channels via cGMP/PI3K pathway.

Ethnopharmacological Relevance: Luteolin (Lut) was recently identified as the major active ingredient of Mosla scabra, which was a typical representative traditional Chinese medicine and had been used to treat pulmonary diseases for thousands of years.

Aim Of The Study: This study was to explore the effects and relative mechanisms of Lut in LPS-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The main characteristic of ALI/ARDS is pulmonary edema, and epithelial sodium channel (ENaC) is a key factor in effective removal of excessive alveolar edematous fluid, which is essential for repairing gas exchange and minimizing damage to the peripheral tissues.

The miR-130a-3p/TGF-βRII Axis Participates in Inhibiting the Differentiation of Fibroblasts Induced by TGF-β1.

Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease that has a poor prognosis. Abnormal activation of transforming growth factor-β1 (TGF-β1) plays a crucial role in fibroblast differentiation. Mesenchymal stem cells (MSCs) are currently being considered for the treatment of PF, but the regulatory mechanisms are poorly understood.

Conditioned Medium of Bone Marrow Mesenchymal Stem Cells Involved in Acute Lung Injury by Regulating Epithelial Sodium Channels miR-34c.

Background: One of the characteristics of acute lung injury (ALI) is severe pulmonary edema, which is closely related to alveolar fluid clearance (AFC). Mesenchymal stem cells (MSCs) secrete a wide range of cytokines, growth factors, and microRNA (miRNAs) through paracrine action to participate in the mechanism of pulmonary inflammatory response, which increase the clearance of edema fluid and promote the repair process of ALI. The epithelial sodium channel (ENaC) is the rate-limiting step in the sodium-water transport and edema clearance in the alveolar cavity; the role of bone marrow-derived MSC-conditioned medium (BMSC-CM) in edema clearance and how miRNAs affect ENaC are still seldom known.

Exosomal MicroRNA: Diagnostic Marker and Therapeutic Tool for Lung Diseases.

Lung diseases are common clinical illnesses with high morbidity and mortality, which seriously threaten human health. In recent years, increasing evidence suggests that exosomes play a pivotal role in intercellular communication by delivering their cargo to pulmonary target cells, such as microRNAs. Physiologically, exosomes have been shown to be a critical mediator in maintaining homeostasis function in the complex thin-walled lung tissue and airway structure.

POSTN Promotes the Proliferation of Spermatogonial Cells by Activating the Wnt/β-Catenin Signaling Pathway.

The self-renewal of spermatogonial cells (SCs) provides the foundation for life-long spermatogenesis. To date, only a few growth factors have been used for the culture of SCs in vitro, and how to enhance proliferation capacity of SCs in vitro needs further research. This study aimed to explore the effects of periostin (POSTN) on the proliferation of human SCs.

Fibrinolysis influences SARS-CoV-2 infection in ciliated cells.

Rapid spread of COVID-19 has caused an unprecedented pandemic worldwide, and an inserted furin site in SARS-CoV-2 spike protein (S) may account for increased transmissibility. Plasmin, and other host proteases, may cleave the furin site of SARS-CoV-2 S protein and γ subunits of epithelial sodium channels (γ ENaC), resulting in an increment in virus infectivity and channel activity. As for the importance of ENaC in the regulation of airway surface and alveolar fluid homeostasis, whether SARS-CoV-2 will share and strengthen the cleavage network with ENaC proteins at the single-cell level is urgently worthy of consideration.

Bone marrow mesenchymal stem cells derived miRNA-130b enhances epithelial sodium channel by targeting PTEN.

Aims: Acute lung injury (ALI) is a clinical syndrome with high morbidity and mortality, and severe pulmonary edema is one of the characteristics. Epithelial sodium channel (ENaC) located on the apical side of alveolar type 2 epithelial (AT2) cells is the primary rate limiting segment in alveolar fluid clearance. Many preclinical studies have revealed that mesenchymal stem cells (MSCs) based therapy has great therapeutic potential for ALI, while the role of ENaC in this process is rarely known.