20 S -Protopanaxadiol, an aglycosylated ginsenoside metabolite, induces hepatic stellate cell apoptosis through liver kinase B1–AMP-activated protein kinase activation

Abstract

BackgroundPreviously, we reported that Korean Red Ginseng inhibited liver fibrosis in mice and reduced the expressions of fibrogenic genes in hepatic stellate cells (HSCs). The present study was undertaken to identify the major ginsenoside responsible for reducing the numbers of HSCs and the underlying mechanism involved.MethodsUsing LX-2 cells (a human immortalized HSC line) and primary activated HSCs, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assays were conducted to examine the cytotoxic effects of ginsenosides. H2O2 productions, glutathione contents, lactate dehydrogenase activities, mitochondrial membrane permeabilities, apoptotic cell subpopulations, caspase-3/-7 activities, transferase dUTP nick end labeling (TUNEL) staining, and immunoblot analysis were performed to elucidate the molecular mechanism responsible for ginsenoside-mediated cytotoxicity. Involvement of the AMP-activated protein kinase (AMPK)-related signaling pathway was examined using a chemical inhibitor and small interfering RNA (siRNA) transfection.Results and conclusionOf the 11 ginsenosides tested, 20S-protopanaxadiol (PPD) showed the most potent cytotoxic activity in both LX-2 cells and primary activated HSCs. Oxidative stress-mediated apoptosis induced by 20S-PPD was blocked by N-acetyl-l-cysteine pretreatment. In addition, 20S-PPD concentration-dependently increased the phosphorylation of AMPK, and compound C prevented 20S-PPD-induced cytotoxicity and mitochondrial dysfunction. Moreover, 20S-PPD increased the phosphorylation of liver kinase B1 (LKB1), an upstream kinase of AMPK. Likewise, transfection of LX-2 cells with LKB1 siRNA reduced the cytotoxic effect of 20S-PPD. Thus, 20S-PPD appears to induce HSC apoptosis by activating LKB1–AMPK and to be a therapeutic candidate for the prevention or treatment of liver fibrosis.

Adenophora Stricta Root Extract Protects Lung Injury from Exposure to Particulate Matter 2.5 in Mice

“…However, benzoic acid glycosides (e.g., vanillic acid 4-β-D-glucopyranoside) generally have low bioavailability due to the hydrophilicity of the conjugated glycosides. In this regard, it has been believed that the biological effects of ingested glycosylated phytochemicals result from the aglycone metabolites produced during absorption [ 37 , 38 ]. Of various phytochemicals aforementioned, not only vanillic acid, but also syringic acid and vanillin have been reported to protect the lungs from toxic stimuli [ 39 , 40 , 41 ].…”

Protective Effects of Red Ginseng Against Tacrine-Induced Hepatotoxicity: An Integrated Approach with Network Pharmacology and Experimental Validation

“…8 Research has shown that RG and its components, such as fermented RG and 20(S)-protopanaxadiol, can exert antioxidative and anti-inflammatory effects on liver tissue, contributing to the overall protection of liver function. [9][10][11] The unique phytochemical profile of RG, comprising saponins (notably ginsenosides), flavonoids, polyacetylenes, and polysaccharides, underpins its therapeutic potential. 12 Another study suggested that the hepatoprotective properties of RG are exerted through the activation of the AMPK pathway, which defends against oxidative damage and supports liver health.…”

Computational and experimental characterization of estrogenic activities of 20(S, R)-protopanaxadiol and 20(S, R)-protopanaxatriol

“…Because ginsenosides possess a common four-ring hydrophobic steroid-like structure with sugar moieties attached at C-3, C-6 or C-20 position, they can be divided into four subtypes as protopanaxadiol (PPD), protopanaxatriol (PPT), oleanolic acid, and octillol [6] . Owing to the diversity of chemical structure, the naturally occurring saponins exhibit a wide range of polarity and hydrophobicity, resulting in their distinct biological activities [7] .…”