Specneuzhenide improves bleomycin-induced pulmonary fibrosis in mice via AMPK-dependent reduction of PD-L1.

BACKGROUND: Pulmonary fibrosis (PF) is an escalating global health issue, characterized by rising rates of morbidity and mortality annually. Consequently, further investigation of potential damage mechanisms and potential preventive strategies for PF are warranted. Specnuezhenide (SPN), a prominent secoiridoid compound derived from Ligustrum lucidum Ait, exhibits anti-inflammatory and anti-oxidative capacities, indicating the potential therapeutic actions on PF. However, the underlying mechanisms of SPN on PF remain unclear. PURPOSE: This work was aimed at investigating the protective actions of SPN on PF and the potential mechanism. METHODS: In vivo, mice were administrated with bleomycin (BLM) to establish PF model. PF mice were treated with SPN (45/90 mg/kg) by gavage. In vitro, we employed TGF-ß1 (10 ng/mL)-induced MLE-12 and PLFs cells, which then were treated with SPN (5, 10, 20 µM). DARTS assay, biofilm interference experiment and molecular docking were performed to investigate the molecular target of SPN. RESULTS: In vivo, we found SPN treatment improved survival rate, alleviated pathological changes through reducing BLM-induced extracellular matrix (ECM) deposition, as well as BLM-induced epithelial-mesenchymal transition (EMT). In vitro, SPN inhibited EMT and lung fibroblast transdifferentiation. Mechanistically, SPN activated the AMPK protein to decrease the abnormally high level of PD-L1. Furthermore, the compound C, known as an AMPK inhibitor, exhibited a significant hindrance to the inhibition of SPN on TGF-ß1-caused fibroblast transdifferentiation and proliferation. This outcome could be attributed to the fact that compound C could eliminate the inhibitory effects of SPN on PD-L1 expression. Interestingly, DARTS assay, biofilm interference experiment and molecular docking results all indicated that SPN could bind to AMPK, which suggested that SPN might be a potential agonist targeting AMPK protein. CONCLUSION: Altogether, the results in our work illustrated that SPN promoted AMPK-dependent reduction of PD-L1 protein, contributing to the inhibition of fibrosis progression. Thus, SPN may represent a potential AMPK agonist for PF treatment.

Cerebral neurotoxicity of amino-modified polystyrene nanoplastics in mice and the protective effects of functional food Camellia pollen.

Accumulating evidence suggests that nanoplastics contribute to an increased risk of brain damage, however, the precise underlying mechanisms remain unclear. Here, we subjected mice to long-term exposure to amino-modified polystyrene nanoplastics (APS-NPs). These nanoplastics were detected in the mouse brain; coupled with the observed upregulation of Alzheimer's disease-associated genes (APP and MAPT). To further explore nanoplastic damage mechanisms and the corresponding protective strategies against these mechanisms in vitro, we used hCMEC/D3 and HT22 cells. Results showed that APS-NPs disrupted tight junction proteins (Occludin and ZO-1) via TLR2/MMP9 axis, resulting in blood-brain barrier permeation; this was significantly mitigated by functional food Camellia pollen treatment. APS-NPs initiated iNOS and nNOS upregulation within neurons resulting in Sirtuin 1 deacetylase inactivation and CBP acetyltransferase stimulation, ultimately leading to Ac-Tau formation. This process was attenuated by Camellia pollen, which also ameliorated the APS-NPs-induced neuronal apoptosis mediated by the p53/Bax/Bcl-2 axis. Network pharmacology analysis of Camellia pollen offered a further theoretical understanding of its potential applications in preventing and treating nervous system disorders, such as Alzheimer's disease. This study established that Camellia pollen protects the brain against APS-NPs-mediated blood-brain barrier damage and alleviates neuronal apoptosis and Alzheimer's disease-like neurotoxicity. This study elucidates the mechanisms underlying polystyrene-induced brain damage and can be used to inform future prevention and treatment strategies.