Search Results (339)

Background: Acute mountain sickness (AMS) is a prevalent and potentially life-threatening condition caused by rapid exposure to high-altitude hypoxia, affecting pulmonary and neurological functions. Tongqiao Jiuxin Oil (TQ), a traditional Chinese medicine formula composed of aromatic and resinous ingredients such as sandalwood, agarwood, frankincense, borneol, and musk, has been widely used in the treatment of cardiovascular and cerebrovascular disorders. Clinical observations suggest its potential efficacy against AMS, yet its pharmacological mechanisms remain poorly understood. Methods: The chemical profile of TQ was characterized using UHPLC-Q-Exactive Orbitrap HRMS. Network pharmacology was applied to predict the potential targets and pathways involved in AMS. A rat model of AMS was established by exposing animals to hypobaric hypoxia (~10% oxygen), simulating an altitude of approximately 5500 m. TQ was administered at varying doses. Physiological indices, oxidative stress markers (MDA, SOD, GSH), histopathological changes, and the expression of hypoxia- and apoptosis-related proteins (HIF-1α, VEGFA, EPO, Bax, Bcl-2, Caspase-3) in lung and brain tissues were assessed. Results: A total of 774 chemical constituents were identified from TQ. Network pharmacology predicted the involvement of multiple targets and pathways. TQ significantly improved arterial oxygenation and reduced histopathological damage in both lung and brain tissues. It enhanced antioxidant activity by elevating SOD and GSH levels and reducing MDA content. Mechanistically, TQ downregulated the expression of HIF-1α, VEGFA, EPO, and pro-apoptotic markers (Bax/Bcl-2 ratio, Caspase-3), while upregulated Bcl-2, the anti-apoptotic protein expression. Conclusions: TQ exerts protective effects against AMS-induced tissue injury by improving oxygen homeostasis, alleviating oxidative stress, and modulating hypoxia-related and apoptotic signaling pathways. This study provides pharmacological evidence supporting the potential of TQ as a promising candidate for AMS intervention, as well as the modern research method for multi-component traditional Chinese medicine. Full article

Cadmium (Cd)-induced pulmonary toxicity is closely associated with ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation (LPO). Luteolin (Lut) is a natural flavonoid compound that exists in many plants. In this study, we used human bronchial epithelial BEAS-2B cells to explore the impact of ferroptosis in the inhibition of Cd-induced BEAS-2B cells proliferation. BEAS-2B cells were exposed to Cd (5 μM) with/without Lut (10 μM), ferroptosis modulators (Ferrostatin-1 (Fer-1)/Erastin), or nuclear factor erythroid 2-related factor 2 (Nrf2) regulators (tert-butylhydroquinone (TBHQ)/ML385). Viability, iron content, reactive oxygen species (ROS), LPO, mitochondrial membrane potential (MMP), and glutathione peroxidase (GSH-PX) activity were assessed. Exposure to Cd significantly decreased cell viability, increased intracellular iron levels, ROS production, and LPO activity, while simultaneously reducing MMP and GSH-PX activity. Fer-1 mitigated Cd-induced cytotoxicity, but Erastin intensified these effects. Mechanistically, Cd exposure suppressed the Nrf2/Solute Carrier Family 7 Member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway, which plays a crucial role in maintaining redox homeostasis. Activation of Nrf2 using TBHQ mitigated oxidative stress and upregulated the expression of key proteins within this pathway, while inhibition of Nrf2 with ML385 exacerbated cellular damage. Notably, Lut treatment could significantly alleviate Cd-induced cytotoxicity, oxidative stress, and downregulation of Nrf2/SLC7A11/GPX4 proteins. These findings demonstrate that ferroptosis is a critical mechanism underlying Cd-mediated lung epithelial injury and identify Lut as a promising therapeutic candidate via its activation of Nrf2-driven antioxidant defense mechanisms. This study provides novel insights into molecular targets for the prevention and treatment of Cd-associated pulmonary disorders. Full article

Objectives: Saffron, a traditional Chinese medicine, is renowned for its pharmacological effects in promoting blood circulation, resolving blood stasis, regulating menstruation, detoxification, and alleviating mental disturbances. Trans-crocetin, its principal bioactive component, exhibits significant anti-hypoxic activity. The clinical development and therapeutic efficacy of trans-crocetin are limited by its instability, poor solubility, and low bioavailability. Conversion of trans-crocetin into trans-sodium crocetinate (TSC) enhances its solubility, stability, and bioavailability, thereby amplifying its anti-hypoxic potential. Methods: This study integrates network pharmacology with in vivo and in vitro validation to elucidate the molecular targets and mechanisms underlying TSC’s therapeutic effects against high-altitude acute lung injury (HALI), aiming to identify novel treatment strategies. Results: TSC effectively reversed hypoxia-induced biochemical abnormalities, ameliorated lung histopathological damage, and suppressed systemic inflammation and oxidative stress in HALI rats. In vitro, TSC mitigated CoCl₂-induced hypoxia injury in human pulmonary microvascular endothelial cells (HPMECs) by reducing inflammatory cytokines, oxidative stress, and ROS accumulation while restoring mitochondrial membrane potential. Network pharmacology and pathway analysis revealed that TSC primarily targets the EGFR/PI3K/AKT/NF-κB signaling axis. Molecular docking and dynamics simulations demonstrated stable binding interactions between TSC and key components of this pathway. ELISA and RT-qPCR confirmed that TSC significantly downregulated the expression of EGFR, PI3K, AKT, NF-κB, and their associated mRNAs. Conclusions: TSC alleviates high-altitude hypoxia-induced lung injury by inhibiting the EGFR/PI3K/AKT/NF-κB signaling pathway, thereby attenuating inflammatory responses, oxidative stress, and restoring mitochondrial function. These findings highlight TSC as a promising therapeutic agent for HALI. Full article

Background/Objectives: This study aimed to evaluate the effects of lung injury induced by insoluble uranium oxide particles on gut microbiota and related metabolites in rats. Methods: The rats were randomly divided into six UO₂ dose groups. A rat lung injury model was established through UO₂ aerosol. The levels of uranium in lung tissues were detected by ICP-MS. The expression levels of the inflammatory factors and fibrosis indexes were measured by enzyme-linked immunosorbent assay. Paraffin embedding-based hematoxylin & eosin staining for the lung tissue was performed to observe the histopathological imaging features. Metagenomic sequencing technology and HM700-targeted metabolomics were conducted in lung tissues. Results: Uranium levels in the lung tissues increased with dose increase. The expression levels of Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), Collagen I, and Hydroxyproline (Hyp) in rat lung homogenate increased with dose increase. Inflammatory cell infiltration and the deposition of extracellular matrix were observed in rat lung tissue post-exposure. Compared to the control group, the ratio of Firmicutes and Bacteroides in the gut microbiota decreased, the relative abundance of Akkermansia_mucinphila decreased, and the relative abundance of Bacteroides increased. The important differential metabolites mainly include αlpha-linolenic acid, gamma-linolenic acid, 2-Hydroxybutyric acid, Beta-Alanine, Maleic acid, Hyocholic acid, L-Lysine, L-Methionine, L-Leucine, which were mainly concentrated in unsaturated fatty acid biosynthesis, propionic acid metabolism, aminoacyl-tRNA biosynthesis, phenylalanine metabolism, and other pathways in the UO₂ group compared to the control group. Conclusions: These findings suggest that uranium-induced lung injury can cause the disturbance of gut microbiota and its metabolites in rats, and these changes are mainly caused by Akkermansia_mucinphila and Bacteroides, focusing on unsaturated fatty acid biosynthesis and the propionic acid metabolism pathway. Full article

Objective: This study aimed to investigate the cardioprotective effects of bosentan, an endothelin receptor antagonist, in a rat model of lung ischemia–reperfusion (I/R) injury, with a focus on myocardial tissue involvement. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: sham, bosentan, I/R, and I/R + bosentan. Lung I/R injury was induced by hilar clamping for 45 min, followed by 60 min of reperfusion. Bosentan (30 mg/kg) was administered intraperitoneally 30 min prior to the procedure. Myocardial tissue was evaluated histopathologically for structural disorganization, inflammation, fibrosis, and edema. TGF-β1 protein levels in myocardial tissue were compared across the groups using β-actin as the loading control. ELISA was used to quantify ET-1, NF-κB, and p53 levels, while spectrophotometric analysis was employed to assess MDA levels and the activities of SOD and CAT enzymes in heart tissue. Results: The I/R group exhibited significant myocardial disorganization, inflammation, and interstitial edema compared to the sham and bosentan groups. Bosentan treatment markedly ameliorated these histopathological alterations. Additionally, the I/R group showed elevated levels of ET-1, NF-κB, p53, and MDA, along with reduced SOD and CAT activities; these changes were significantly attenuated by bosentan administration. Bosentan treatment significantly reduced myocardial ET-1 levels (from 136.88 ± 5.02 to 120.18 ± 2.67 nmol/g, p = 0.003), NF-κB levels (from 0.87 ± 0.04 to 0.51 ± 0.03 ng/mg, p = 0.002), and TGF-β1 expression (from 1.72 ± 0.10 to 0.91 ± 0.08 relative units, p = 0.001). Moreover, bosentan increased antioxidant enzyme activities, elevating SOD levels from 21.45 ± 1.23 to 32.67 ± 1.45 U/mg protein (p = 0.001) and CAT levels from 15.22 ± 0.98 to 25.36 ± 1.12 U/mg protein (p = 0.002). Conclusions: Bosentan exerts cardioprotective effects in rats subjected to lung I/R injury by reducing myocardial damage, inflammation, and oxidative stress. These findings suggest that bosentan may serve as a potential therapeutic agent for preventing remote organ injury associated with pulmonary I/R. Full article

Bronchopulmonary dysplasia (BPD) remains a significant complication of preterm birth, characterized by impaired alveolar and vascular development, chronic lung inflammation, and long-term respiratory morbidity. Corticosteroids, both systemic and inhaled, have been widely investigated as potential therapeutic agents due to their anti-inflammatory properties and their emerging role in modulating oxidative stress. This narrative review explores the current evidence regarding the use of inhaled and systemic corticosteroids in the prevention and management of BPD, analyzing their efficacy, safety profiles, and long-term outcomes. While systemic corticosteroids, particularly dexamethasone, have demonstrated benefits in reducing ventilator dependence and lung inflammation, concerns regarding adverse neurodevelopmental effects have limited their routine use. Inhaled steroids have been proposed as a safer alternative, but their role in altering the disease trajectory remains controversial. A better understanding of the optimal timing, dosage, and patient selection is essential to maximize benefits while minimizing risks. Future research should focus on optimizing dosing strategies and identifying subgroups of preterm infants who may derive the greatest benefit from corticosteroid therapy. Full article

Primary graft dysfunction (PGD) remains a major complication after lung transplantation. Donor lung ischemia followed by reperfusion drives oxidative stress and inflammatory responses. The pathophysiology is influenced by various donor-, procedure-, and recipient-related factors, which complicates the identification of biomarkers for evaluation of donor lung injury or therapeutic interventions to minimize PGD. This review provides an overview of the molecular pathways that contribute to PGD pathophysiology, including those involved in loss of endothelial–epithelial membrane integrity, neutrophil infiltration, and the development of pulmonary edema. Full article

Background: Acute lung injury (ALI) is driven by inflammatory cascades and reactive oxygen species (ROS) generation, with the progression to severe cases markedly increasing mortality. Sinapine thiocyanate (ST), a bioactive natural compound isolated from Sinapis Semen Albae (SSA), demonstrates both anti-inflammatory and antioxidant pharmacological activities. However, no monotherapeutic formulation of ST has been developed to date. A dry powder inhaler (DPI) enables targeted pulmonary drug delivery with excellent stability profiles and high inhalation efficiency. Methods: ST was purified and prepared as inhalable dry powder particles via an antisolvent crystallization technique. The therapeutic mechanisms of ST against ALI were elucidated by network pharmacology and pharmacokinetic analyses, with the therapeutic efficacy of the ST DPI in ALI mitigation being validated using LPS-induced rat models. Results: The ST DPI showed ideal aerodynamic characteristics. Notably, ST exhibited a three-compartment (triexponential) pharmacokinetic profile following both intravenous tail vein injection and inhalation administration. Furthermore, the inhaled formulation displayed a prolonged systemic residence time, which confers therapeutic advantages for pulmonary disease management. Furthermore, the inhalation administration of ST demonstrated a 2.7-fold increase in AUC compared with oral gavage, with a corresponding enhancement in systemic exposure. The ST DPI formulation demonstrated significant therapeutic efficacy against ALI in rats by downregulating inflammatory cytokines and modulating oxidative stress levels, mechanistically achieved through the MAPK-mediated regulation of cellular apoptosis via a positive feedback loop. Conclusions: The unique triexponential plasma level profiles of an ST DPI provide a promising pharmacokinetics-based therapeutic strategy for ALI, leveraging its marked efficacy in attenuating inflammation, oxidative stress, and pulmonary injury. Full article

Bronchopulmonary dysplasia (BPD) remains a significant complication of premature birth and neonatal intensive care. While much is known about the drivers of lung injury, few studies have addressed the interrelationships between oxidative stress, inflammation, and downstream events, such as endoplasmic reticulum (ER) stress. In this review, we explore the concept of a “destructive cycle” in which these drivers self-amplify to push the lung into a state of maladaptive repair. Animal models, primarily the hyperoxic rat pup model, support a sequential progression from the generation of reactive oxygen species (ROS) and inflammation to endoplasmic reticulum (ER) stress and mitochondrial injury. We highlight how these intersecting pathways offer not just therapeutic targets but also opportunities for interventions that reprogram system-wide responses. Accordingly, we explore the potential of systems pharmacology therapeutics (SPTs) to address the multifactorial nature of BPD. As a prototype SPT, we describe the development of N-acetyl-L-lysyl-L-tyrosyl-L-cysteine amide (KYC), a systems chemico-pharmacology drug (SCPD), which is selectively activated in inflamed tissues and modulates key nodal targets such as high-mobility group box-1 (HMGB1) and Kelch-like ECH-associated protein-1 (Keap1). Collectively, the data suggest that future therapies may require a coordinated, network-level approach to break the destructive cycle and enable proper regeneration rather than partial repair. Full article

Acute lung injury is a severe disease with a high mortality rate, which can result in increased oxidative stress and further mitochondrial damage and cell apoptosis. L-Clausenamide is an amide from the fruit wampee. This study combined network pharmacology, molecular docking, and in vitro study to elucidate the effect of combating acute lung injury and the underlying mechanism of L-Clausenamide. Network pharmacology indicated that the 152 targets can treat acute lung injury through regulating oxidative stress. Based on PPI analysis and screening of the central target, AKT1 is the key target of the underlying mechanism. KEGG and GO enrichment analysis demonstrated that apoptosis is an important pathway for this curing effect. In the in vitro study, treatment with L-Clausenamide alleviates intracellular ROS accumulation, mitochondrial membrane potential loss, mitochondrial morphological distortion, ATP decrease, and the CASP3 activity. The SPR analysis was performed to validate the binding between AKT1 and L-Clausenamide. The Western blot result showed that L-Clausenamide increases the phosphorylation of Akt and decreases cleavage of CASP3. L-Clausenamide can alleviate lipopolysaccharide (LPS)-induced acute lung injury through targeting AKT1 and show an improvement in mitochondrial abnormality and inhibition against ROS-activated caspase-3-dependent apoptosis activation. Full article

In chronic respiratory diseases (CRDs), oxidative stress and inflammation are closely linked, driving disease onset, progression, and comorbidities. Oxidative stress activates inflammatory pathways, while chronic inflammation promotes further reactive oxygen species (ROS) production, creating a vicious cycle leading to airway remodeling, reduced lung function, and exacerbations. This review highlights the central roles of inflammation and oxidative stress in chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA). In COPD, chronic hypoxemia associates with emphysema, appearing with disease progression. In OSA, beyond systemic consequences, pulmonary inflammation and oxidative stress contribute to lung injury as well. Although COPD and OSA are distinct conditions, some patients present with “overlap syndrome”, a term used in this review to describe the coexistence of both. This combination poses unique diagnostic and therapeutic challenges. We also examine the role of hypoxia and its transcriptional effects via hypoxia-inducible factors (HIFs) in promoting oxidative stress and inflammation. Finally, we explore how artificial intelligence (AI) offers promising tools to improve diagnosis, monitoring, and management of CRDs and may help elucidate mechanistic links between hypoxia, inflammation, and oxidative stress, contributing to more personalized therapeutic strategies. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Background: Sepsis-induced acute lung injury (ALI) is a serious disease constituting a heavy burden on society due to high mortality and morbidity. Inflammation and oxidative stress constitute key pathological mechanisms in ALI caused by sepsis. LL-37 can improve the survival of septic mice. Nevertheless, its function and underlying mechanism in sepsis-evoked ALI is elusive. Methods: The human A549 alveolar epithelial cell line was treated with LL-37 or ZBP1 recombinant vector under LPS exposure. Then, the effects on cell oxidative stress injury, inflammatory response, and autophagy were analyzed. RNA-seq analysis was performed to detect the differentially expressed genes (DEGs) between the LPS and LPS/LL-37 groups. Furthermore, the effects of LL-37 on cecal ligation and the puncture (CLP)-constructed ALI model were explored. Results: LL-37 attenuated LPS-evoked oxidative injury in human alveolar epithelial cells by increasing cell viability and suppressing ROS, malondialdehyde, and lactate dehydrogenase levels and apoptosis. Moreover, LPS-induced releases of pro-inflammatory IL-18, TNF-α, and IL-1β were suppressed by LL-37. Furthermore, LPS’s impairment of autophagy was reversed by LL-37. RNA-seq analysis substantiated 1350 differentially expressed genes between the LPS and LPS/LL-37 groups. Among them was ZBP1, a significantly down-regulated gene with the largest fold change. Moreover, LL-37 suppressed LPS-increased ZBP1 expression. Importantly, ZBP1 elevation restrained LL-37-induced autophagy in LPS-treated cells and abrogated LL-37-mediated protection against LPS-evoked oxidative injury and inflammation. LL-37 ameliorated abnormal histopathological changes, tissue edema, the lung injury score, oxygenation index (PaO2/FiO2), and glycemia contents in the CLP-constructed ALI model, which were offset through ZBP1 elevation via its activator CBL0137. Additionally, LL-37 suppressed inflammation and oxidative stress in lung tissues, concomitant with autophagy elevation and ZBP1 down-regulation. Conclusions: LL-37 may alleviate the progression of sepsis-evoked ALI by attenuating pulmonary epithelial cell oxidative injury and inflammatory response via ZBP1-mediated autophagy activation, indicating a promising approach for the therapy of ALI patients. Full article

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway. Full article

Acute lung injury (ALI) is a fatal respiratory disease caused by excessive inflammation. Chelerythrine chloride (CH), an isoquinoline alkaloid, exhibits diverse biological activities. The research focused on assessing CH’s therapeutic effects against LPS-mediated ALI in mice and its underlying mechanisms. The anti-inflammatory effects of CH were evaluated both in LPS-induced RAW264.7 cells and ALI mouse model. An amount of 2.5 μM CH significantly inhibited the secretion of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β in RAW264.7 cells. CH treatment notably mitigated the thickened alveolar septa and reduced edema in LPS-induced ALI in mice. Activity-based protein profiling (ABPP) technology was employed to identify the targets of CH. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was one of the direct targets of CH identified by ABPP. CH could downregulate the production of pyruvate. Furthermore, CH reduced the extracellular acidification rate (ECAR) while increasing the oxygen consumption rate (OCR) in LPS-stimulated RAW264.7 cells. All results suggest that CH mitigates LPS-induced ALI by targeting GAPDH and inhibiting glycolysis. This study reveals preliminary anti-inflammatory mechanisms of CH and its therapeutic potential for ALI. Full article