Fucoidan Alleviates Acetaminophen-Induced Hepatotoxicity via Oxidative Stress Inhibition and Nrf2 Translocation

Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that leads to severe hepatotoxicity at excessive doses. Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. However, the impacts of fucoidan on APAP-induced liver injury have not been sufficiently addressed. In the present study, male Institute of Cancer Research (ICR) mice aged 6 weeks were subjected to a single APAP (500 mg/kg) intraperitoneal injection after 7 days of fucoidan (100 or 200 mg/kg/day) or bicyclol intragastric administration. The mice continued to be administered fucoidan or bicyclol once per day, and were sacrificed at an indicated time. The indexes evaluated included liver pathological changes, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum, levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in the liver, and related proteins levels (CYP2E1, pJNK and Bax). Furthermore, human hepatocyte HL-7702 cell line was used to elucidate the potential molecular mechanism of fucoidan. The mitochondrial membrane potential (MMP) and nuclear factor-erythroid 2-related factor (Nrf2) translocation in HL-7702 cells were determined. The results showed that fucoidan pretreatment reduced the levels of ALT, AST, ROS, and MDA, while it enhanced the levels of GSH, SOD, and CAT activities. Additionally, oxidative stress-induced phosphorylated c-Jun N-terminal protein kinase (JNK) and decreased MMP were attenuated by fucoidan. Although the nuclear Nrf2 was induced after APAP incubation, fucoidan further enhanced Nrf2 in cell nuclei and total expression of Nrf2. These results indicated that fucoidan ameliorated APAP hepatotoxicity, and the mechanism might be related to Nrf2-mediated oxidative stress.

Protective Effects of Fucoidan against Hydrogen Peroxide-Induced Oxidative Damage in Porcine Intestinal Epithelial Cells

“…A similar result has also been reported recently, in which H 2 O 2 upregulates cellular NRF2 protein levels but downregulates the mRNA expression of SOD1 in IPEC-1 cells [50]. Studies have demonstrated that fucoidan prevents oxidative damage by activating the NRF2 signaling pathway in human hepatocytes [22] and human lung fibroblast cells [20]. In the present study, fucoidan also promoted the translocation of NRF2 to nuclei in IPEC-1 cells exposed to oxidative stress, as supported by its significantly high nuclear fluorescence intensity.…”

“…Likewise, Roy Chowdhury et al [20] found that a bacterial fucose-rich polysaccharide protects human lung fibroblast cells against H 2 O 2 -induced apoptosis and necrosis by directly scavenging ROS. The biological function of fucoidan against oxidative stress has also been reported in mesenchymal stem cells [21], normal human hepatocytes [22], and mouse adipocytes [23]. Michel et al [24] initially showed that fucoidan is totally excreted after oral administration, since it cannot be fermented by intestinal bacterial flora in humans.…”

Effects of Fucoidans from Five Different Brown Algae on Oxidative Stress and VEGF Interference in Ocular Cells

“…However, independent of all of the results from simple cell-free assays, fucoidans may exhibit antioxidative activity by cellular effects. Accordingly, fucoidan has been shown to increase the expression of superoxide dismutase (SOD) in several experimental models and activate the transcription factor nuclear factor erythroid 2-like 2 (Nrf2), the “master regulator” of the antioxidative stress response [27,28,29,30,31,32]. Both the overall protective effect of our fucoidans on OMM-1 and the limited protective effect on ARPE19 cells (only found for Saccharina latissima fucoidan) could be explained via these pathways.…”

Preventive Effects of Three Polysaccharides on the Oxidative Stress Induced by Acrylamide in a Saccharomyces cerevisiae Model

“…The up-regulation of intracellular GSH depends on the regulation of Nrf2 to γ-glutamyl cysteine synthetase the rate-limiting enzymes of GSH biosynthesis [ 37 ]. Previous studies have confirmed that SIP and fucoidan can activate Nrf2 and mediate GSH level rise in chemo-drug mediated oxidative stress [ 14 , 38 ] From 10 h to 18 h, the GSH level of normal cells gradually increased, while the GSH level of cells in the AA group gradually decreased, which may be due to AA damaged the cell genes. AA is metabolized to GA and binds to DNA and proteins more actively, leading to glycidamide-DNA adduct formation, which could be participated in ACR mutagenicity [ 36 ].…”