Fortunellin ameliorates LPS-induced acute lung injury, inflammation, and collagen deposition by restraining the TLR4/NF-κB/NLRP3 pathway.

OBJECTIVE: Acute lung injury (ALI) is the prevalent respiratory disease of acute inflammation with high morbidity and mortality. Fortunellin has anti-inflammation property, but its role in ALI remains elusive. Thus, this study clarified the function of fortunellin on ALI pathogenesis. METHODS: The ALI mouse model was established by lipopolysaccharide (LPS) induction, and lung tissue damage was evaluated utilizing hematoxylin-eosin (HE) staining. The edema of lung tissue was measured by the lung wet/dry (W/D) ratio. The lung capillary permeability was reflected by the protein content in bronchoalveolar lavage fluid (BALF). Inflammatory cell infiltration was measured by the evaluation of the content of myeloperoxidase (MPO), neutrophils, and leukocytes in BALF. Cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The secretions of inflammatory cytokines were quantified using enzyme-linked immunosorbent assay (ELISA) assays. Lung tissue collagen deposition was evaluated by Masson staining. RESULTS: Fortunellin attenuated LPS-induced lung tissue damage and reduced the W/D ratio, the content of MPO in lung tissue, the total protein contents in BALF, and the neutrophils and leukocytes number. Besides, fortunellin alleviated LPS-stimulated lung tissue apoptosis, inflammatory response, and collagen deposition. Furthermore, Fortunellin repressed the activity of the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway in the LPS-stimulated ALI model and LPS-induced RAW264.7 cells. Moreover, fortunellin attenuated LPS-stimulated tissue injury, apoptosis, inflammation, and collagen deposition of the lung via restraining the TLR4/NF-κB/NLRP3 pathway. CONCLUSION: Fortunellin attenuated LPS-stimulated ALI through repressing the TLR4/NF-κB/NLRP3 pathway. Fortunellin may be a valuable drug for ALI therapy.

Songorine ameliorates LPS-induced sepsis cardiomyopathy by Wnt/ß-catenin signaling pathway-mediated mitochondrial biosynthesis.

Septic cardiomyopathy (SCM) is manifested by impairment of cardiac contractile function with myocardial mitochondrial dysregulation. Natural product, songorine (SGR), a diterpenoid alkaloid derived from the lateral root of Aconitum carmichaeli, has been reported for the treatment of heart failure. Here, the protective role of SGR in heart injury of SCM was investigated and its underlying action of mechanism was explored. Firstly, the mouse and cardiomyocytes (H9C2 cell) SCM model induced by LPS were established to evaluate the therapeutic effect of SGR. The in vivo results exhibited that SGR rescued the survival rate of SCM mice, restored the loss of ejection fraction (EF) and fractional shortening (FS), and reduced left ventricular systolic diameter and left ventricular diastole diameter (LVIDs, LVIDd) by echocardiography. SGR improved the mitochondrial biosynthesis and myocardial fiber structure and arranged them neatly by transmission electron microscope (TEM). Further, SGR inhibited inflammatory targets myeloperoxidase (MPO) and tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and plasminogen activator inhibitor-1 (PAI-1). And SGR activated the mitochondrial biosynthesis-related peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), ß-catenin, and matrix metallopeptidase 2 (MMP2) proteins. Meanwhile, the in vitro results showed that SGR promoted the increased the myocardial H9C2 cell viability, and mitochondrial biosynthesis and structure. SGR also blocked the inflammatory factors and reversed PGC-1α, ß-catenin, and MMP2 in vitro, while SGR alleviated the myocardial cell apoptosis via flow cytometry. The findings indicate that SGR mitigates sepsis-caused myocardial damage by Wnt/ß-catenin signaling pathway-mediated mitochondrial biosynthesis. SGR may be a promising candidate for treatment of SCM.

Sivelestat sodium alleviated lipopolysaccharide-induced acute lung injury by improving endoplasmic reticulum stress.

Acute lung injury (ALI) is a common inflammatory respiratory disorder characterized by a high incidence and mortality rate. This study aimed to investigate the potential therapeutic effects of the neutrophil elastase inhibitor Sivelestat sodium (SIV) in improving endoplasmic reticulum stress (ERS) while treating lipopolysaccharide (LPS)-induced ALI. An ALI model was established using LPS induction. The effects of SIV on ALI were observed both in vivo and in vitro, along with its impact on ERS. Lung tissue damage was assessed using Hematoxylin-eosin (H&E) staining. Lung edema was measured by the lung wet/dry weight ratio. The expression levels of protein kinase R-like ER kinase (PERK), Phospho-protein kinase R-like ER kinase (p-PERK), activating transcription factor 4 (ATF4), eukaryotic translation initiation factor 2α (EIF2a), phosphorylated α subunit of eukaryotic initiation factor 2α (P-EIF2a), and C/EBP homologous protein (CHOP) were analyzed by Western blotting in vivo and in vitro. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in Lung tissue samples supernatants were measured by ELISA. Oxidative stress markers were measured by ELISA. Apoptosis was measured using the TUNEL assay. Apoptosis-associated proteins B-cell lymphoma-2 (Bcl-2)、Bcl2-associated × (Bax)、caspase-3 were evaluated through Western blotting in vivo and in vitro. The expression levels of ERS-related proteins, including p-PERK, ATF4, P-EIF2a, and CHOP, were significantly increased in the LPS-induced ALI model. However, SIV markedly reduced the expression levels of these proteins, suppressing the LPS-induced ERS response. Further investigations revealed that SIV exerted a protective effect on ALI by alleviating lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress levels. However, when SIV was co-administered with Tunicamycin (TUN), TUN blocked the beneficial effects of SIV on ERS and reversed the protective effects of SIV on ALI. In conclusion, SIV alleviated lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress in LPS-induced ALI by improving ERS.

Penehyclidine hydrochloride protects against lipopolysaccharide-induced acute lung injury by promoting the PI3K/Akt pathway.

INTRODUCTION: Acute lung injury (ALI) attracted attention among physicians because of its high mortality. We aimed to determine whether the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway is involved in the protective effects of penehyclidine hydrochloride (PHC) against lipopolysaccharide (LPS)-induced ALI. METHODS: H&E staining was used to observed pathological changes in the lung tissues. ELISA was used to evaluate the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF). White-light microscopy was performed to observe the TUNEL-positive nuclei. The viability of NR8383 alveolar macrophages was determined by using CCK-8. The levels of MPO, MDA, SOD, and GSH-Px were analyzed using ELISA kits. Western blotting was used to evaluate the ERS-associated protein levels and the phosphorylation of PI3K and Akt. RESULTS: PHC administration defended against LPS-induced histopathological deterioration and increased pulmonary edema and lung injury scores, while all of these beneficial effects were inhibited by LY. In addition, PHC administration mitigated oxidative stress as indicated by decreases in lung myeloperoxidase (MPO) and malondialdehyde (MDA) concentrations, and increases in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) concentrations. It also alleviated LPS-induced inflammation. PHC administration attenuated apoptosis-associated protein levels, improved cell viability, and decreased the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells. Furthermore, PHC inhibited ERS-associated protein levels. Meanwhile, the protection of PHC against inflammation, oxidative stress, apoptosis, and ERS was inhibited by LY. Moreover, PHC administration increased PI3K and Akt phosphorylation, indicating that the upregulation of the PI3K/Akt pathway, while this pathway was inhibited by LY. CONCLUSION: PHC significantly activates the PI3K/Akt pathway to ameliorate the extent of damage to pulmonary tissue, inflammation, oxidative stress, apoptosis, and ERS in LPS-induced ALI.

Konjac glucomannan defends against high-fat diet-induced atherosclerosis in rabbits by promoting the PI3K/Akt pathway.

Atherosclerosis (AS) is the main cause of cardiovascular disease and cerebral infarction, which seriously endanger human health. This study aimed to investigate konjac glucomannan (KGM) defends against high-fat diet-induced AS in rabbits by promoting the PI3K/Akt pathway. KGM administration reduced the degree of AS indicated by reducing the plaques and foam cells, the tunica intima thickness, and the tunica intima/tunica media thickness ratio in the aorta, and enlarging the lumen of the aorta. In addition, KGM administration regulated blood lipids, ameliorated inflammation indicated by reducing the levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, CRP, and VCAM-1, and attenuated endothelial injury, simultaneously mitigated oxidative stress indicated by decreasing MPO activity and the concentrations of MDA and increasing the GSH-Px and SOD concentrations. Moreover, KGM promotes the phosphorylation of PI3K and AKT. However, these effects of KGM on rabbits with high-fat diet-induced AS were blocked by LY294002. In conclusion, KGM defends against high-fat diet-induced AS in rabbits by promoting the PI3K/Akt pathway.