Ginkgolide C attenuates lipopolysaccharide‑induced acute lung injury by inhibiting inflammation via regulating the CD40/NF‑κB signaling pathway

Abstract

Excessive lung inflammation caused by endotoxins, including lipopolysaccharide (LPS), mediates the detrimental effects of acute lung injury (ALI), as evidenced by severe alveolar epithelial cell injury. CD40, a member of the tumor necrosis factor receptor superfamily, serves as a central activator in triggering and transducing a series of severe inflammatory events during the pathological processes of ALI. Ginkgolide C (GC) is an efficient and specific inhibitor of CD40. Therefore, the present study aimed to investigate whether GC alleviated LPS-induced ALI, as well as the potential underlying mechanisms. LPS-injured wild-type and CD40 gene conditional knockout mice, and primary cultured alveolar epithelial cells isolated from these mice served as in vivo and in vitro ALI models, respectively. In the present study, histopathological assessment, polymorphonuclear neutrophil (PMN) infiltration, lung injury score, myeloperoxidase activity, wet-to-dry (W/D) weight ratio and hydroxyproline (Hyp) activity were assessed to evaluate lung injury. In addition, immunohistochemistry was performed to evaluate intracellular adhesion molecule-1, vascular cell adhesion molecule-1 and inducible nitric oxide synthase expression levels, and TNF-α, IL-1β, IL-6 ELISAs and western blotting were conducted to elucidate the signaling pathway. The results demonstrated that GC alleviated LPS-induced lung injury, as evidenced by improvements in ultrastructural characteristics and histopathological alterations of lung tissue, inhibited PMN infiltration, as well as reduced lung injury score, W/D weight ratio and hydroxyproline content. In LPS-injured alveolar epithelial cells, GC significantly reduced IκBα phosphorylation, IKKβ activity and NF-κB p65 subunit translocation via downregulating CD40, leading to a significant decrease in downstream inflammatory cytokine levels and protein expression levels. In conclusion, the results of the present study demonstrated that GC displayed a protective effect against LPS-induced ALI via inhibition of the CD40/NF-κB signaling pathway; therefore, the present study suggested that the CD40/NF-κB signaling pathway might serve as a potential therapeutic target for ALI.

Integrated metabolomic and transcriptomic analysis reveals variation in the metabolites and genes of Platycodon grandiflorus roots from different regions

“…Some studies have showed potential benefits of beta-ionone in human health regarding important pharmacological activities: antiinflammatory, anti-cancer, antibacterial, antifungal, and ginkgolide c has been reported to display various pharmacological actions of reducing lipid accumulation, increasing lipolysis, inhibiting inflammation, anti-cancer. [45][46][47] Meanwhile, jasmonic acid has showed a broad spectrum of activity, anti-cancer, anti-inflammatory and anti-ageing. 48 These secondary metabolites may be the material basis for the difference in efficacy between PGn and PGb.…”

“…Lipids, for example, contain beta‐ionone, ginkgolide c, jasmonic acid, alpha‐curcumene, capsidiol, and citraconic acid, etc. Some studies have showed potential benefits of beta‐ionone in human health regarding important pharmacological activities: anti‐inflammatory, anti‐cancer, antibacterial, antifungal, and ginkgolide c has been reported to display various pharmacological actions of reducing lipid accumulation, increasing lipolysis, inhibiting inflammation, anti‐cancer 45‐47 . Meanwhile, jasmonic acid has showed a broad spectrum of activity, anti‐cancer, anti‐inflammatory and anti‐ageing 48 .…”

Ginkgolide C Alleviates Acute Lung Injury Caused by Paraquat Poisoning via Regulating the Nrf2 and NF-κB Signaling Pathways

“…The lung injury score was applied to evaluate the severity of lung injury as previously described [ 23 ]. According to the thickness of alveolar wall, the amount of inflammatory infiltration, and the level of hemorrhaging, the lung score was calculated.…”

“…A nuclear and cytoplasmic protein extraction kit (Beyotime Institute of Biotechnology) was applied to extract the cytoplasmic and nuclear proteins as previous described [ 23 ]. And a BCA assay kit was applied to determine the protein concentration.…”

“…An increasing body of evidence suggested that its leaf extracts had various biological properties such as cardioprotective effects, antineurovascular insults, and anticancer activities [ 20 – 22 ]. Ginkgolide C (GC) is a flavonoid monomer extracted from Ginkgo biloba leaf, and we previously discovered and identified that it could protect against ALI induced by LPS via inhibiting the CD40/NF- κ B signaling pathway [ 23 ]. However, it is still unclear whether GC could alleviate the ALI induced by PQ poisoning.…”