Salvianolic acid A attenuates TNF-α- and D-GalN-induced ER stress-mediated and mitochondrial-dependent apoptosis by modulating Bax/Bcl-2 ratio and calcium release in hepatocyte LO2 cells.
Salvianolic acid (Sal A) is a water-soluble compound extracted from Radix Salvia miltiorrhiza (danshen), which has been widely used to treat acute hepatitis and hepatic damage in traditional Chinese medicine. The aim of the present study was to delineate the antiapoptotic signaling pathways involved in Sal A's hepato-protective action in hepatocyte LO2 cells and to further elucidate the mechanism by which Sal A elicits the antiapoptotic effects on hepatocytes. Here, the study showed that Sal A had antiapoptotic effects on the TNF-α/D-GalN-treated LO2 cells. Moreover, Western blotting demonstrated that the levels of p-eIF2α, ATF4, GRP78, CHOP and caspase-4 were markedly decreased in Sal A group. Additionally, the decrease of the cell mitochondrial membrane permeability and increase of ΔΨm were detected in Sal A-treated cells by high-content screening (HCS) analysis. And the levels of cleaved-caspase-9, cleaved-caspase-3, apoptosis-inducing factor (AIF), Apaf-1, and Cytc (cyto) were downregulated, while Cytc (mito) was upregulated by Sal A via Western blotting. Furthermore, the decreased levels of Bax/Bcl-2 ratio and calcium release were measured in Sal A-treated cells. In summary, Sal A attenuates TNF-α- and D-GalN-induced both ER stress and mitochondrial-dependent apoptosis by suppression of Bax/Bcl-2 ratio and prevention of calcium release, which support the notion that Sal A could be developed into a novel hepatic protectant.
Department of Preclinical Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd., Nanjing, 210023, China.
Xiaojing
X
Yan
Zequn
Z
Jiang
Lei
L
Bi
Ye
Y
Yang
Weiping
W
Chen
D017209:Apoptosis / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005688:Galactosamine; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D002109:Caffeic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007773:Lactates; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C066201:salvianolic acid A; D005688:Galactosamine