Hepatoprotective effect of chiisanoside from Acanthopanax sessiliflorus against LPS/D-GalN-induced acute liver injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways.

BACKGROUND: In China, Acanthopanax sessiliflorus is a delicious wild vegetable. It is also used to treat inflammation and pain. Chiisanoside (CSS) is the main constituent of the leaf of A. sessiliflorus. Combined use of lipopolysaccharide and d-galactosamine (LPS/D-GalN) can induce acute liver failure in human beings, and there are no reports on the protective effect of CSS against LPS/D-GalN-induced acute liver injury in mice. RESULTS: Chiisanoside pretreatment evidently reduced the activities of alanine transaminase (ALT) and aspartate transaminase (AST) in the changes induced by LPS/D-GalN, and these histopathological changes induced by LPS/GalN were significantly weakened. Catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) activities increased, and malondialdehyde (MDA) activity decreased after CSS treatment compared with LPS/D-GalN treatment. Pretreatment with CSS also inhibited the expression levels of inflammatory factors. The administration of CSS prevented the phosphorylated expression of inhibitor kappa B (IκB) kinase, and led to a significant increase in heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor2 (Nrf2) nuclear translocation. CONCLUSION: The protective effects of CSS are attributed to its antioxidative effect and inflammatory suppression in Nuclear factor kappa beta (NF-κB) and Nrf2/HO-1 signaling pathways. Chiisanoside might therefore be a potential ingredient for drug and food development against acute liver injury in the future. © 2018 Society of Chemical Industry.

Simultaneous quantification method for eleutheroside B, eleutheroside E, chiisanoside, and sesamin using reverse-phase high-performance liquid chromatography coupled with ultraviolet detection and integrated pulsed amperometric detection.

We developed a method combining ultraviolet (UV) detection and integrated pulsed amperometric detection (IPAD) to simultaneously analyze eleutheroside B, eleutheroside E, chiisanoside, and sesamin. The gradient elution system allowed complete separation of all target components within 35 min, and showed limits of detection of 0.006-0.020 µg/mL and limits of quantification of 0.018-0.050 µg/mL. The linear regression coefficients of determination were 0.9990-0.9998. All inter- and intra-day precision values were below 4.89%, and the average recoveries were 97.79-104.40%. The developed approach exhibits excellent reproducibility, sensitivity, and selectivity without requiring any complicated pre-treatment, and is therefore expected to be helpful as a tool for establishing appropriate content criteria for Acanthopanax species.

Chiisanoside Mediates the Parkin/ZNF746/PGC-1α Axis by Downregulating MiR-181a to Improve Mitochondrial Biogenesis in 6-OHDA-Caused Neurotoxicity Models In Vitro and In Vivo: Suggestions for Prevention of Parkinson's Disease.

The degeneration of dopamine (DA) neurons is known to be associated with defects in mitochondrial biogenesis caused by aging, environmental factors, or mutations in genes, leading to Parkinson's disease (PD). As PD has not yet been successfully cured, the strategy of using small molecule drugs to protect and restore mitochondrial biogenesis is a promising direction. This study evaluated the efficacy of synthetic chiisanoside (CSS) identified in the leaves of Acanthopanax sessiliflorus to prevent PD symptoms. The results show that in the 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate the reactive oxygen species generation and apoptosis of SH-SY5Y cells, thereby lessening the defects in the C. elegans model including DA neuron degeneration, dopamine-mediated food sensitivity behavioral disorders, and shortened lifespan. Mechanistically, we found that CSS could restore the expression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), a key molecule in mitochondrial biogenesis, and its downstream related genes inhibited by 6-OHDA. We further confirmed that this is due to the enhanced activity of parkin leading to the ubiquitination and degradation of PGC-1α inhibitor protein Zinc finger protein 746 (ZNF746). Parkin siRNA treatment abolished this effect of CSS. Furthermore, we found that CSS inhibited 6-OHDA-induced expression of miR-181a, which targets parkin. The CSS's ability to reverse the 6-OHDA-induced reduction in mitochondrial biogenesis and activation of apoptosis was abolished after the transfection of anti-miR-181a and miR-181a mimics. Therefore, the neuroprotective effect of CSS mainly promotes mitochondrial biogenesis by regulating the miR-181a/Parkin/ZNF746/PGC-1α axis. CSS potentially has the opportunity to be developed into PD prevention agents.

A new 3,4-seco-lupane triterpenene glycosyl ester from the leaves of Eleutherococcus sessiliflorus.

A new minor 3,4-seco-lupane triterpenene glycosyl ester, named sessiloside-A1 (1), along with three known 3,4-seco-lupane triterpenenes were isolated from the which alcohol extract of the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y. Hu by silica gel column chromatography, and their structures were determined by spectroscopic methods (UV, IR, NMR and HRMS). Compound 1 was elucidated to be ß-D-glucopyranosyl ester of chiisanogenin. At the same time, a new efficient two-step enzymatic hydrolysis method was established to transform chiisanoside (2) → divaroside (3) → 1.

New insights into potential nutritional effects of dietary saponins in protecting against the development of obesity.

Excessive energy intake, poor physical exercise and genetics/epigenetics are instrumental for the development of obesity. Because of rapidly emerging evidences related to off-target effects and toxicity of anti-obesity drugs, there is a need to search for more effective and targeted drugs for treatment of obesity. Substantial studies have found the nutritional effects of dietary saponins (bio-detergents) in terms of decreasing the synthesis of lipids, suppressing adipogenesis, inhibiting intestinal absorption of lipids, and promoting fecal excretion of bile acids and triglycerides. Dietary saponin have been approved as potent pancreatic lipase inhibitors, disaccharidase enzyme inhibitors, antagonistic to in vitro lipogenesis and in vivo appetite suppressants, antioxidants, immune-regulators, prevent fatty liver formation, protects epithelial vasculature and regulate body weight. Many dietary saponins, such as sibutramine, morgoside, sessiloside, soysaponin B, and diosgenin, have treatment potential against the development of obesity. Excellent scientific achievements have been developed for a better understanding the mechanism of saponins in preventing obesity.

Hepatoprotective effect of chiisanoside against acetaminophen-induced acute liver injury in mice.

This study was designed to investigate the hepatoprotective effect of chiisanoside (CSS) and its possible mechanisms on acetaminophen (APAP)-induced acute liver damage in mice. The serum activities of alanine transaminase (ALT), aspartate transaminase (AST), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and the hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA) were determined using the commercially available assay kits. The hepatic mRNA levels were measured by RT-PCR. The hepatic protein expressions of nuclear factor-kappa B (NF-κB), MAPK and their phosphorylated isoforms were evaluated by western blot assays. The results indicated that CSS (240 mg/kg) exhibited the hepatoprotective effects by inhibiting oxidative stress and inflammation on APAP-induced acute liver injury. Furthermore, the anti-inflammatory activity of CSS is largely related to the regulation of the NF-κB and MAPKs signaling pathways. These findings suggested that CSS possessed hepatoprotective effect against APAP-induced hepatotoxicity in mice.

Study on antidepressant activity of chiisanoside in mice.

The antidepressant-like effect of chiisanoside from the leaves of Acanthopanax sessiliflorus was evaluated by using mice models of depression, forced swim test (FST) and tail suspension test (TST). The results showed that treatment with chiisanoside at dose of 5.0 mg/kg significantly decreased immobility time in the FST and TST. Pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist) and N-methyl-D-aspartic acid (NMDA, an agonist at the glutamate site) effectively reversed the antidepressant-like effect of chiisanoside (5.0 mg/kg). Moreover, chiisanoside treatment did not change the locomotor activity. And chiisanoside (5.0 mg/kg) also effectively increased the dopamine (DA) and γ-aminobutyric acid (GABA) levels in mice brains exposed to the FST and TST in the co-treatment groups. Then we designed lipopolysaccharide (LPS)-induced antidepressant behavioral experiment, the results showed that LPS significantly increased immobility duration in the TST and FST. Chiisanoside administration could effectively reduce serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; at the same time, the changes of related indexes of oxidative stress are improved, such as superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, chiisanoside effectively down-regulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and nuclear factor-κB (NF-κB) in hippocampal. In conclusion, chiisanoside displayed significant antidepressant-like effect, which was probably related to the DAergic, GABAergic and glutamatergic systems. And the mechanism of anti-depressant effect of chiisanoside might be via the alterations of animal behaviors, hippocampus inflammation, oxidative stress and neurotrophy, which might be attributed by the BDNF/TrkB/NF-κB pathway.