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OBJECTIVES: Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This study explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+]CSF) and red blood cells (RBCs) ([Mg2+]RBC) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements. METHODS: Animals were assigned to either normal or low Mg diet for 30 - 45 days. Following this, animals maintained on low Mg diet were supplemented with various Mg compounds. [Mg2+]CSF and [Mg2+]RBC were measured at baseline and following Mg administration. Anxiety-like behavior and cognitive function were also evaluated. RESULTS: The present study showed that a short-term and moderate reduction in Mg dietary intake results in a significant decline in [Mg2+]CSF and [Mg2+]RBC and the emergence of anxiety-like behavior in comparison to animals maintained on normal Mg diet. Supplementation with SC/BW extract significantly elevated [Mg2+]CSF and improved animal performance in the novel object recognition test in comparison with animals maintained on reduced Mg intake and supplemented with various Mg compounds. DISCUSSION: These observations indicate that brain [Mg2+] is more sensitive to a short-term and moderate reduction in Mg dietary intake than previously thought and emphasizes the importance of dietary Mg in replenishing brain Mg2+ reserves.

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Proteomics monitoring of an elite adventure athlete (age 33 years) was conducted over a 28-week period that culminated in the successful, solo, unassisted, and unsupported two month trek across the Antarctica (1500 km). Training distress was monitored weekly using a 19-item, validated training distress scale (TDS). Weekly dried blood spot (DBS) specimens were collected via fingerprick blood drops onto standard blood spot cards. DBS proteins were measured with nano-electrospray ionization liquid chromatography tandem mass spectrometry (nanoLC-MS/MS) in data-independent acquisition (DIA) mode, and 712 proteins were identified and quantified. The 28-week period was divided into time segments based on TDS scores, and a contrast analysis between weeks five and eight (low TDS) and between weeks 20 and 23 (high TDS, last month of Antarctica trek) showed that 31 proteins (n = 20 immune related) were upregulated and 35 (n = 17 immune related) were downregulated. Protein-protein interaction (PPI) networks supported a dichotomous immune response. Gene ontology (GO) biological process terms for the upregulated immune proteins showed an increase in regulation of the immune system process, especially inflammation, complement activation, and leukocyte mediated immunity. At the same time, GO terms for the downregulated immune-related proteins indicated a decrease in several aspects of the overall immune system process including neutrophil degranulation and the antimicrobial humoral response. These proteomics data support a dysfunctional immune response in an elite adventure athlete during a sustained period of mental and physical distress while trekking solo across the Antarctica.

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Green tea and (-)-epigallocatechin-3-gallate (EGCG) have been studied for their obesity-related health effects. Many green tea extract (GTE)-based dietary supplements are commercially-available. Although green tea beverage has a long history of safe use, a growing number of case-reports have linked GTE-based supplements to incidents of hepatotoxicity. Animal studies support the hepatotoxic potential of GTE and EGCG, but the mechanisms remain unclear. Here, we examined the hepatotoxic effects of EGCG in C57BL/6J mice and evaluated changes in hepatic antioxidant response and mitochondria structure and function. Intragastric dosing with EGCG (500 - 750 mg/kg) once daily for 3 d caused hepatic inflammation, necrosis, and hemorrhage. Hepatotoxicity was associated with increased oxidative stress and decreased superoxide dismutase and glutathione peroxidase levels. Real-time PCR and transmission electron microscopy showed decreased hepatic mitochondria copy number in EGCG-treated mice. The mRNA levels of marker genes of respiratory complex I and III, sirtuin 3, forkhead box O3a, and peroxisome-EGCG-treated mice. Sirtuin 3 protein levels were also decreased by EGCG. Our data indicate the mitochondria may be a target for EGCG, and that inhibition of mitochondria function/antioxidant response may be important for the hepatotoxicity of bolus EGCG.

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Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements.

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