Ginsenoside Rk1 ameliorates paracetamol-induced hepatotoxicity in mice through inhibition of inflammation, oxidative stress, nitrative stress and apoptosis

Abstract

BackgroundFrequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time.MethodsMice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, all mice treated with 250 mg/kg APAP exhibited severe liver injury after 24 h, and hepatotoxicity was assessed.ResultsOur results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-1β compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group.ConclusionThe results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.

Preventive effect of flavonoids from Wushan Shencha (Malus doumeri leaves) on CCl4‐induced liver injury

“…Inflammatory cytokines TNF‐α and IL‐1β increased significantly within 24 hr of liver injury. Therefore, blocking the production of TNF‐α or IL‐1β may attenuate liver injury (Hu et al, ). In this study, the flavonoids of Wushan Shencha effectively enhanced the expression of IκB‐α and reduced the expression of COX‐2, TNF‐α, and IL‐1β in mice with liver injury.…”

Ginsenoside Rk1 bioactivity: a systematic review

“…The most common study design was in vitro study with 22 studies ( Ahn et al, 2016 ; Ju et al, 2012 ; Kang et al, 2007 ; Kang et al, 2006 ; Kim et al, 2012 ; Kim et al, 2009 ; Kim et al, 2008 ; Kim et al, 2013b ; Ko et al, 2009 ; Kwak & Pyo, 2016 ; Lee et al, 2009 ; Lee et al, 2010 ; Lee, 2014 ; Lim et al, 2009 ; Liu et al, 2007 ; Park et al, 2002 ; Ponnuraj et al, 2014 ; Quan et al, 2015 ; Ryu et al, 2016 ; Siddiqi et al, 2014 ; Toh et al, 2011 ; Xue et al, 2017 ), while in vivo study was less common with only two studies ( Jing et al, 2006 ; Kim et al, 2010 ). The remaining four articles were both in vitro and in vivo studies ( Bao et al, 2005 ; Hu et al, 2017 ; Maeng et al, 2013 ; Park et al, 2015 ). A summary of the included studies was presented in Table 1 .…”

“…We used the GRADE method ( Guyatt et al, 2011 ) to assess the quality of the included studies. Sixteen studies were categorized as high quality ( Hu et al, 2017 ; Kang et al, 2006 ; Kim et al, 2009 ; Kim et al, 2008 ; Ko et al, 2009 ; Kwak & Pyo, 2016 ; Lee et al, 2009 ; Lee, 2014 ; Lim et al, 2009 ; Liu et al, 2007 ; Maeng et al, 2013 ; Park et al, 2002 ; Quan et al, 2015 ; Ryu et al, 2016 ; Toh et al, 2011 ; Xue et al, 2017 ). Twelve studies ( Ahn et al, 2016 ; Bao et al, 2005 ; Jing et al, 2006 ; Ju et al, 2012 ; Kang et al, 2007 ; Kim et al, 2012 ; Kim et al, 2010 ; Kim et al, 2013b ; Lee et al, 2010 ; Park et al, 2015 ; Ponnuraj et al, 2014 ; Siddiqi et al, 2014 ) were categorized as moderate quality.…”

“…They measured the extent of edema and noticed that the pretreatment with red ginseng saponin extract or G-Rk1 suppresses TPA-induced mouse ear edema, and when administering G-Rk1 orally, the formation of edema was blocked. Hu et al (2017) showed that in acetaminophen (APAP) induced liver injury in mice, G-Rk1 can be used as a protective agent, as it significantly reduced the levels of tumor necrosis factor (TNF-α) to 87 ng/L and when treated with 10 mg/kg G-Rk1 compared to 156 ng/L when treated with 250 mg/kg APAP. A significant reduction of interleukin-1β (IL-1β) was observed with G-Rk1 ( Hu et al, 2017 ).…”

Protective effect of ginsenoside Rk1, a major rare saponin from black ginseng, on cisplatin‐induced nephrotoxicity in HEK‐293 cells

“…Ginsenosides in white ginseng underwent deglycosylation, dehydration, and isomerization to generate many rare ginsenosides during the steaming process, of these rare ginsenosides, Rk1 (Figure 1A) was major one produced from protopanaxadiol‐type ginsenosides in the above reaction 19 . It is well‐known to have various pharmacological activities including anti‐cancer, 20 anti‐inflammatory 21 and anti‐platelet aggregation 22 …”