ABSTRACT
Emerging evidence has demonstrated that iron overload plays an important role in oxidative stress in the liver. This study aimed to explore whether fluoride-induced hepatic oxidative stress is associated with iron overload and whether grape seed proanthocyanidin extract (GSPE) alleviates oxidative stress by reducing iron overload. Forty Kunming male mice were randomly divided into 4 groups and treated for 5 weeks with distilled water (control), sodium fluoride (NaF) (100 mg/L), GSPE (400 mg/kg bw), or NaF (100 mg/L) + GSPE (400 mg/kg bw). Mice exposed to NaF showed typical poisoning changes of morphology, increased aspartate aminotransferase and alanine aminotransferase activities in the liver. NaF treatment also increased MDA accumulation, decreased GSH-Px, SOD and T-AOC levels in liver, indicative of oxidative stress. Intriguingly, all these detrimental effects were alleviated by GSPE. Further study revealed that NaF induced disorders of iron metabolism, as manifested by elevated iron level with increased hepcidin but decreased ferroportin expression, which contributed to hepatic oxidative stress. Importantly, the iron dysregulation induced by NaF could be normalized by GSPE. Collectively, these data provide a novel insight into mechanisms underlying fluorosis and highlight the potential of GSPE as a naturally occurring prophylactic treatment for fluoride-induced hepatotoxicity associated with iron overload.
Subject(s)
Grape Seed Extract/pharmacology , Iron Overload/chemically induced , Liver Diseases/etiology , Liver Diseases/prevention & control , Liver , Oxidative Stress/drug effects , Phytotherapy , Proanthocyanidins/pharmacology , Sodium Fluoride/adverse effects , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Cation Transport Proteins/metabolism , Hepcidins/metabolism , Iron/metabolism , Iron Overload/complications , Iron Overload/metabolism , Liver/enzymology , Liver/pathology , Male , MiceABSTRACT
To investigate whether grape seed proanthocyanidin extract (GSPE) antagonizes fluoride-induced oxidative injury by regulating iron metabolism, human embryo hepatic cells (L-02) were incubated with sodium fluoride (NaF, 80 mg/L) and/or GSPE (100 µmol/L) for 24 h. Results showed the glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and total antioxidant capacity (T-AOC) level of the NaF group were significantly lower than that of the control group (P < 0.05), while malondialdehyde (MDA) content increased in the NaF group compared with the control group (P < 0.05). Moreover, the indexes mentioned above showed opposite changes in the NaF + GSPE group. In addition, iron content significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Furthermore, hepcidin (coded by HAMP) messenger RNA (mRNA) expression significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Ferroportin 1 (coded by FPN1) mRNA expression significantly decreased in the NaF group compared to the control group (P < 0.05) and significantly increased in the NaF + GSPE group compared to the NaF group (P < 0.05). These results indicate that GSPE provides significant cellular protection against oxidative stress induced by excessive fluoride via the iron metabolism regulation.