Genipin protects against sepsis via the inhibition of endoplasmic reticulum stress to attenuate splenocyte apoptosis

Abstract

Objective This study is undertaken to elucidate the protective effect and molecular mechanism of genipin against cecal ligation and puncture (CLP)-induced sepsis. Methods Male C57BL/6 mice were assigned to three groups: vehicle-treated sham group, vehicle-treated CLP group, and genipin-treated CLP group. Genipin (2.5 mg/kg) and vehicle (0.9% saline) were respectively administered to corresponding group via the tail vein at 0 h and 20 h after the CLP. First, for the survival experiment, mortality was monitored up to 120 h after the CLP procedure. Second, based on the survival test, 36 h time point after CLP was selected for further tests. The serum concentrations of tumor necrosis factor α (TNF- α) and interleukin 6 (IL-6) were detected by enzym-linked immunosorbent assay (ELISA). The pathological damages to lung and liver tissue were detected by hematoxylineosin staining (HE staining). The expression levels of endoplasmic reticulum (ER) stress-related proteins such as glucose regulated protein78 (GRP78), protein kinase r-like endoplasmic reticulum kinase (PERK), p-eukaryotic initation factor 2α (p-eIF2α), and C/EBP homologous protein (CHOP) were determined by Western Blot. Detection of splenocyte apoptosis was performed by using the terminal-deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. Results Compared with the vehicle-treated CLP group, genipin significantly improved the survival of septic mice, decreased the serum levels of TNF-α and IL-6, and alleviated histopathological damages to lung and liver such as edema and inflammatory cell infiltration. Moreover, genipin significantly downregulated the expression levels of splenic GRP78, PERK, p-eIF2α, and CHOP, and lessened ERinduced splenocyte apoptosis. Conclusion Genipin significantly attenuates sepsis-induced organ injury and the excessive inflammatory response and improves the outcome of sepsis. The effect mechanisms of genipin against sepsis are probably associated with decreasing splenocyte apoptosis by attenuating ER stress to further block the ER stress-induced apoptosis.

Keywords

• sepsis
• genipin
• endoplasmic reticulum stress
• unfolded protein response