Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF-α-mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage.

Zhang J ，Zhang S ，Bi J ，Gu J ，Deng Y ，Liu C ... -  《-》

Improved protective effects of American ginseng berry against acetaminophen-induced liver toxicity through TNF-α-mediated caspase-3/-8/-9 signaling pathways.

Similar to the leaves of P. Quinquefolius, American ginseng berry (AGB) is another important part of P. Quinquefolius with alternative therapeutic potential. The liver protection capabilities of the former have been demonstrated previously, however, the later has not yet been evaluated. Based on our previous observation, the present work was designed to evaluate the hepatic protective effects for novel mechanisms of AGB in acetaminophen (APAP)-induced liver injury in vivo. All mice were divided into four groups as follows: normal group, APAP group and APAP + AGB (150 mg/kg and 300 mg/kg) groups. AGB were orally administered for one week before exposure to APAP (250 mg/kg). Severe liver injury was observed and hepatotoxicity was evaluated after 24 h through evaluating the biochemical markers, protein expressions levels and liver histopathology. Our study results clearly demonstrated that AGB pretreatment ameliorated APAP-induced hepatic injury as evidenced by decreasing plasma alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) compared to the APAP group. Western blotting analysis showed that pretreatment with AGB decreased the expressions levels of TNF-α and nuclear transcription factor-κB (NF-κB p65) in liver tissues. Meanwhile, the protein expression levels of caspases, cytochrome c, and Bax were elevated by AGB treatment for seven days, while the protein expression level of Bcl-2 was inhibited comparison with that in APAP group. Furthermore, supplement of AGB resulted in increase of superoxide dismutase (SOD) and glutathione (GSH), while decrease of malondialdehyde (MDA) content and the expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 E1 (CYP2E1). The results of histopathological staining demonstrated that AGB pretreatment inhibited APAP-induced hepatocyte infiltration, congestion, and necrosis. The present study demonstrated that AGB pretreatment protected liver cells against APAP-induced hepatotoxicity through inhibition of oxidative stress, inflammation responses via TNF-α-mediated caspase-3/-8/-9 signaling pathways.

Xu XY ，Wang Z ，Ren S ，Leng J ，Hu JN ，Liu Z ，Chen C ，Li W ... -  《-》

Saponins (Ginsenosides) from the Leaves of Panax quinquefolius Ameliorated Acetaminophen-Induced Hepatotoxicity in Mice.

Xu XY ，Hu JN ，Liu Z ，Zhang R ，He YF ，Hou W ，Wang ZQ ，Yang G ，Li W ... -  《-》

Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse.

Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti-oxidative and anti-inflammatory activities of luteolin, using acetaminophen-treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-α, nuclear factor kappa B (NF-κB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen-induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice.

Tai M ，Zhang J ，Song S ，Miao R ，Liu S ，Pang Q ，Wu Q ，Liu C ... -  《-》

Mangiferin ameliorates acetaminophen-induced hepatotoxicity through APAP-Cys and JNK modulation.

An overdose of the most popular analgesic, acetaminophen (APAP), is one of the leading causes of acute liver failure. It is well established that glutathione is exhausted by APAP-reactive intermediate N‑acetyl‑p‑benzoquinone-imine (NAPQI). This leads to elevated phosphorylated-c-Jun N-terminal kinase (p-JNK), which further activates reactive oxygen species (ROS), initiates an inflammatory response, and finally leads to severe hepatic injury. The present study was conducted to investigate the protective role of mangiferin (MAN), a naturally occurring xanthone and anti-oxidant, on APAP-induced hepatotoxicity. C57BL/6 mice were pretreated with or without MAN at 1 h prior to APAP challenge. MAN was administered at a dose of 12.5-50 mg/kg along with APAP at a dose of 400 mg/kg. According to the ALT/AST ratio, 25 mg/kg MAN was the most potent dose for further experiments. Serum ALT and AST depletion were observed in APAP + MAN (25 mg/kg)-treated mice at 6, 12, and 24 h. Early (1 h after APAP treatment) GSH depletion by APAP overdose was restored by MAN treatment, which reduced APAP-Cys adduct formation and promoted protection. p-JNK downregulation and AMPK activation were observed in MAN-treated mice, which could mechanistically reduce oxidative stress and inflammation. MAN up-regulated liver GSH and SOD and reduced lipid peroxidation. HO-1 protein and p47 phox mRNA expression indicated that MAN regulated oxidative stress along with JNK deactivation. The expression of inflammatory response genes TNF-α, IL-6, MCP-1, CXCL-1, and CXCL-2 reached the basal levels after MAN treatment. mRNA, protein, and serum levels of IL-1β were reduced, and NF-κB expression was similar to that of the MAN-treated APAP mice. MAN post-treatment (1 h after APAP treatment) also protected the mice from hepatotoxicity. In conclusion, MAN had a protective and therapeutic role in APAP-induced hepatotoxicity by improving the metabolism of acetaminophen and APAP-Cys adduct formation followed by JNK-mediated oxidative stress and inflammation.

Chowdhury A ，Lu J ，Zhang R ，Nabila J ，Gao H ，Wan Z ，Adelusi Temitope I ，Yin X ，Sun Y ... -  《-》