Respiratory Research最新文献

Objective: This study aimed to combine network pharmacology with in vitro experiments to identify the key targets and potential mechanisms of salidroside (Sal) in the treatment of acute lung injury (ALI).

Methods: Potential targets related to Sal and ALI were retrieved from the ChEMBL, SuperPRED, SwissTargetPrediction, GeneCards, OMIM, and CTD databases. Overlapping targets were imported into the STRING database and Cytoscape software to construct a protein-protein interaction (PPI) network and identify core targets. Functional enrichment analysis of these core genes, including GO and KEGG pathways, was performed using the DAVID database. Two genes, MAPK14 and GPX4, directly relevant to subsequent validation, were selected for molecular docking analysis. Furthermore, an in vitro model of ALI was established using LPS-induced alveolar type II epithelial cells to verify the protective mechanism of Sal.

Results: A total of 355 potential targets associated with Sal in ALI treatment were identified. In vitro experiments showed that, compared to the LPS group, the Sal group exhibited significantly reduced secretion of IL-6, ROS, p-MAPK, MDA, and Fe²⁺, along with increased GPX4 expression and attenuated lung injury.

Conclusion: Integrated network pharmacology and experimental validation suggest that Sal pretreatment alleviates inflammatory response and oxidative stress, likely through regulation of the MAPK/GPX4 signaling pathway, thereby providing protection against lung tissue injury.

Background: Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype-highlighting the critical need for novel therapeutic approaches. The retinoic acid receptor-related orphan receptor gamma (RORγ) has been implicated in various cancers, but its role and mechanism in NSCLC remain unclear.

Methods: RORγ expression and its correlation with patient prognosis in NSCLC were assessed by integrating public database bioinformatics analysis, immunohistochemistry, and Western blot. The functional roles of RORγ in NSCLC proliferation, migration, and invasion were determined in vitro through genetic overexpression, pharmacological inhibition, or genetic silencing of RORγ, assessed by cell counting, colony formation, wound healing, and transwell assays. The underlying mechanism was investigated using RNA sequencing, chromatin immunoprecipitation, and rescue experiments with exogenous nerve growth factor (NGF) supplementation or NGF overexpression. In vivo, the anti-tumor efficacy of RORγ inhibition was evaluated using subcutaneous xenograft and experimental metastasis models.

Results: We identify RORγ as a key driver of NSCLC progression. Integrative bioinformatics and immunohistochemical analysis revealed that RORγ is highly expressed in NSCLC tissues and that its expression correlates with poor patient prognosis. Functionally, elevated RORγ significantly enhanced the proliferation, migration, and invasion capabilities of NSCLC cells. Conversely, treatment with the RORγ antagonist or genetic silencing of RORγ potently suppressed these malignant phenotypes both in vitro and in vivo. Mechanistically, RORγ directly binds to the promoter region of NGF, stimulates NGF gene transcription, and thereby promotes NSCLC progression. RORγ antagonists suppress NGF expression and inhibit its downstream signaling pathways, whereas exogenous NGF supplementation or overexpression of NGF notably reverses the inhibitory effects of RORγ antagonists on NSCLC cells.

Conclusion: Taken together, these results establish RORγ as a critical regulator of NSCLC and a promising therapeutic target for NSCLC treatment.

The ubiquitin-proteasome system is the primary system that mediates protein turn over through proteolytic activities in the 20S proteasome that catalyzes peptide hydrolysis. It is crucial for maintaining protein homeostasis and regulates many cellular processes including DNA repair, cell proliferation, and inflammatory responses. Immunoproteasome, a special class of proteasome with three distinct catalytic subunits β1i (LMP2), β2i (MECL-1), and β5i (LMP7), is induced in most cells in response to various stimuli. The subunits replacement alters proteasomal cleavage preference and enhances the generation of major histocompatibility complex I (MHC I) antigenic peptides. Immunoproteasome is involved in pathogenesis of inflammatory diseases by regulating T cells differentiation, macrophages polarization, proinflammatory cytokine production, and management of oxidative stress. In this review, we will discuss the impact of immunoproteasome dysfunctions in pulmonary diseases, such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Selective inhibition of immunoproteasome has the potential to serve as a therapeutic tool to address these significant health challenges. This review underscores the substantial role of the immunoproteasome in mediating the progression of various human lung diseases and highlights its potential as a therapeutic target, offering promising avenues for intervention in response to these health challenges.

Background: Bleomycin (BLM), a widely used antitumor drug, has been demonstrated to induce pulmonary toxicity in both chemotherapy patients and experimental animals, leading to acute lung injury (ALI). However, the lack of effective treatment options limits its clinical application. While peroxiredoxin 1 (Prdx1), a novel damage-associated molecular pattern (DAMP), has been shown to exacerbate acute liver and kidney injury by promoting inflammatory responses, its role in BLM-induced ALI remains unclear.

Methods: An ALI mouse model was established via intratracheal instillation of BLM (5 mg/kg). Prdx1 gene-knockout mice, recombinant murine Prdx1 protein (rPrdx1), and Prdx1-neutralizing monoclonal antibody were utilized to investigate the role of Prdx1 in BLM-induced ALI. Further mechanistic insights were explored through single-cell RNA sequencing analysis.

Results: BLM-induced damage to bronchial epithelial cells triggered Prdx1 release, which subsequently activated the NOD1/NF-κB signaling pathway in macrophages, promoting the release of inflammatory cytokines and exacerbating pulmonary inflammation and pathological damage. These findings were confirmed by single-cell RNA sequencing. Genetic knockout of Prdx1 or administration of Prdx1-neutralizing monoclonal antibody protected mice from BLM-induced ALI, and this protective effect was attenuated by introducing rPrdx1.

Conclusion: These findings identify Prdx1 as a potential therapeutic target for BLM-induced ALI, offering a strategy to mitigate its pulmonary toxicity and facilitate the broader clinical application of BLM.