Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and is primarily caused by cigarette smoking (CS). Neurocognitive comorbidities such as anxiety and cognitive impairments are common among people with COPD. CS-induced lung inflammation and oxidative stress may “spill-over” into the systemic circulation, driving the onset of these comorbidities. We investigated whether a prophylactic treatment with the NADPH Oxidase 2 (NOX2) inhibitor, apocynin, could prevent CS-induced neurocognitive impairments. Adult male BALB/c mice were exposed to CS (9 cigarettes/day, 5 days/week) or room air (sham) for 8 weeks with co-administration of apocynin (5 mg/kg, intraperitoneal injection once daily) or vehicle (0.01% DMSO in saline). Following 7 weeks of CS exposure, mice underwent behavioral testing to assess recognition and spatial memory (novel object recognition and Y maze, respectively) and anxiety-like behaviors (open field and elevated plus maze). Mice were then euthanized, and blood, lungs, and brains were collected. Apocynin partially improved CS-induced lung neutrophilia and reversed systemic inflammation (C-reactive protein) and oxidative stress (malondialdehyde). Apocynin exerted an anxiolytic effect in CS-exposed mice, which was associated with restored microglial profiles within the amygdala and hippocampus. Thus, targeting oxidative stress using apocynin can alleviate anxiety-like behaviors and could represent a novel strategy for managing COPD-related anxiety disorders.

Background: Anaplastic lymphoma kinase (ALK) is a validated oncogenic driver in non-small cell lung cancer and other malignancies, making it a clinically relevant target for small-molecule inhibition. Methods: Here, we report a computational discovery pipeline integrating structure-based virtual screening, machine learning-guided prioritization, molecular dynamics simulations, and binding free energy analysis to identify potential ALK inhibitors from a natural product-derived subset of the ZINC20 database. We trained and benchmarked eleven machine learning models, including tree-based, kernel-based, linear, and neural architectures, on curated bioactivity datasets of ALK inhibitors to capture nuanced structure-activity relationships and prioritize candidates beyond conventional docking metrics. Results: Six compounds were shortlisted based on binding affinity, solubility, bioavailability, and synthetic accessibility. Molecular dynamics simulations over 100 ns revealed stable ligand engagement, with limited conformational fluctuations and consistent retention of the protein’s structural integrity. Key catalytic residues, including GLU105, MET107, and ASP178, displayed minimal fluctuation, while hydrogen bonding and residue interaction analyses confirmed persistent engagement across all ligand-bound complexes. Binding free energy estimates identified ZINC3870414 and ZINC8214398 as top-performing candidates, with ΔG_total values of –46.02 and –46.18 kcal/mol, respectively. Principal component and dynamic network analyses indicated that these compounds restrict conformational sampling and reorganize residue communication pathways, consistent with functional inhibition. Conclusions: These results highlight ZINC3870414 and ZINC8214398 as promising scaffolds for further optimization and support the utility of integrating machine learning with dynamic and network-based metrics in early-stage kinase inhibitor discovery.

Chronic obstructive pulmonary disease (COPD) is a systemic condition with significant extrapulmonary comorbidities. White adipose tissue (WAT) dysfunction, driven by cigarette smoke (CS) exposure, may contribute to systemic inflammation and disease progression. This study investigates whether oxidative stress mediates lung–adipose tissue cross-talk in COPD and whether targeting this pathway can mitigate both pulmonary and metabolic dysfunction. Male BALB/c mice were exposed to CS for 8 or 24 weeks, with or without apocynin, an NADPH oxidase inhibitor. Lung and WAT tissues were analysed for inflammation, oxidative stress, adipokine expression, and mitochondrial function. Phosphoproteomic profiling was performed on lung tissue. In vitro, conditioned media from CS-exposed bronchial epithelial cells and oxidatively primed adipocytes were used to assess reciprocal effects on adipocytes and epithelial cells. CS exposure induced airway inflammation, glucose intolerance, dyslipidaemia, and WAT dysfunction, including increased lipolysis, oxidative stress, and adipokine imbalance. Apocynin treatment reduced oxidative stress, normalised adipokine profiles, and restored mitochondrial markers in WAT. Phosphoproteomic analysis revealed activation of MAPK, TNF, and Apelin signalling pathways in the lungs. Conditioned media experiments confirmed bidirectional cross-talk: epithelial-derived factors impaired adipocyte function, while dysfunctional adipocytes triggered oxidative stress and apoptosis in bronchial epithelial cells.CS-induced oxidative stress drives a pathological feedback loop between the lungs and WAT, contributing to COPD progression and systemic metabolic dysfunction. Targeting redox-sensitive pathways may offer therapeutic strategies to disrupt this lung-adipose axis and improve outcomes in COPD.

Pulmonary rehabilitation (PR) improves exercise tolerance and dyspnoea in chronic obstructive pulmonary disease (COPD) but does not address the elevated cardiovascular disease (CVD) risk. Vascular dysfunction, an early CVD feature, is driven by oxidative stress—a shared pathogenic mechanism in COPD and CVD. Carnosine, a bioactive dipeptide with antioxidant and pH-buffering properties, may enhance muscle performance and protect against vascular injury. The present study sought to determine whether carnosine supplementation combined with exercise training could modify early CVD features in a preclinical COPD model. Male BALB/c mice were exposed to room air or cigarette smoke (CS; 9 cigarettes/day, 5 days/week, 8 weeks) with or without carnosine (1 mg/ml in drinking water) and with or without treadmill exercise training (50% maximal speed; 30 min/day, 5 days/week). After 8 weeks, blood pressure, exercise capacity, resting heart rate, lung inflammation, systemic oxidative stress, aortic endothelial function, and platelet activation were assessed. CS impaired weight gain, reduced exercise capacity, elevated resting heart rate, and induced airway inflammation (P <0.0001). CS also caused severe endothelial dysfunction and platelet activation (P <0.0001). Exercise alone did not reverse these vascular abnormalities. In contrast, carnosine plus exercise restored weight gain, exercise capacity, and heart rate; preserved endothelial function; and prevented platelet adhesion and activation, without altering airway inflammation. Exercise training alone is insufficient to counteract CS-induced vascular injury. Carnosine supplementation provides synergistic vascular protection, highlighting its potential as an adjunct to PR to mitigate oxidative stress-driven CVD risk in COPD.