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Genipin attenuates mitochondrial-dependent apoptosis, endoplasmic reticulum stress, and inflammation via the PI3K/AKT pathway in acute lung injury.

Abstract：

:The protective effects of genipin against lipopolysaccharide (LPS)-induced acute lung injury (ALI) have been reported; however, the mechanism is unclear. Genipin performs its pharmacological effects via activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. In the present study, we aimed to determine whether the PI3K/AKT pathway is involved in the protective effects of genipin against mitochondrial-dependent apoptosis, endoplasmic reticulum stress (ERS), and inflammation in ALI. We constructed in vivo and in vitro models of LPS-induced ALI. PI3K/AKT signaling was inhibited using LY294002. Pretreatment with genipin increased AKT phosphorylation, indicating that PI3K/AKT signaling was upregulated. Genipin pretreatment prevented LPS-induced histopathological deterioration, increased pulmonary edema, and decreased oxygenation index, all of which were inhibited using LY294002. In addition, genipin pretreatment attenuated LPS-mediated mitochondrial apoptosis, as indicated by improved mitochondrial dysfunction, downregulation of BAX (BCL2 associated X, apoptosis regulator), upregulation of BCL2 (BCL2 apoptosis regulator), inhibited the release of cytochrome c, activation of caspase-3, and cell apoptosis. Genipin pretreatment inhibited the LPS-induced upregulation of AF4/FMR2 family member 4 (CHOP), glucose-regulated protein, 78 kDa (GRP78), and X-box binding protein 1 (XBP1) levels, indicating ERS suppression. Moreover, genipin pretreatment alleviated LPS-induced inflammation, indicating by blockade of nuclear factor kappa b (NF-κB) signaling activation and reduced tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 levels in the lung and bronchoalveolar lavage fluid. LY294002 could inhibit these genipin-induced protective effects against apoptosis, ERS, and inflammation. Thus, genipin significantly activates PI3K/AKT signaling to ameliorate mitochondria-dependent apoptosis, ERS, and inflammation in LPS-induced ALI.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Luo X,Lin B,Gao Y,Lei X,Wang X,Li Y,Li T

doi

10.1016/j.intimp.2019.105842

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

105842

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(19)30752-0

journal_volume

pub_type

杂志文章

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Genipin attenuates mitochondrial-dependent apoptosis, endoplasmic reticulum stress, and inflammation via the PI3K/AKT pathway in acute lung injury.