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In clinical studies, aged garlic extract (AGE) has been shown to improve endothelial dysfunction. The activation of nuclear factor erythroid 2 like 2 (Nrf2)-dependent gene expression is a proposed mechanism for maintaining vascular homeostasis. S−1-propenylcysteine (S1PC) and S-allylcysteine (SAC) are two predominant sulfur-containing amino acids present in AGE. However, it remains unclear as to whether the two sulfur amino acids activate Nrf2 in cells. Nitric oxide (NO) is an important signaling molecule and one of the activators of the Nrf2 pathway. In a previous study, we examined the effects of the two sulfur amino acids on NO signaling for modulating the Nrf2-dependent antioxidant response. Neither S1PC nor SAC were found to affect the expression of Nrf2-regulated genes, such as heme oxygenase-1 (HMOX1) in human umbilical vein endothelial cells. However, S1PC was found to augment HMOX1 expression, induced by NO donors, such as NOR3. NOR3 was found to induce the nuclear accumulation of NRF2 protein and concomitantly enhance the degradation of BTB domain and CNC homolog 1 (BACH1), a transcriptional repressor that competes with NRF2. Notably, on our previous study, S1PC enhanced the NOR3-induced downregulation of BACH1, but did not further enhance the NOR3-induced accumulation of NRF2. The findings of that study indicated that the S1PC-induced degradation of BACH1 may provide a basis for the antioxidant effects of AGE. Thus, in this review, we aimed to provide a current overview of the antioxidant effects of AGE and sulfur-containing amino acids. [ABSTRACT FROM AUTHOR]

The nuclear factor erythroid 2–related factor 2 (Nrf2)–antioxidant response element (ARE) pathway defends cells against oxidative stress and regulates the cellular redox balance. Activation of this pathway induces a variety of antioxidant enzymes, resulting in the protection of our bodies against oxidative damage. It has been reported that aged garlic extract (AGE), a garlic preparation that is rich in water-soluble cysteinyl moieties, reduces oxidative stress and helps to ameliorate of cardiovascular, renal and hepatic diseases. We hypothesized that AGE enhances the expression of antioxidant enzymes via the Nrf2-ARE pathway in human umbilical vein endothelial cells in culture. Gene expression of antioxidant enzymes was measured using real-time polymerase chain reaction. Nuclear accumulation of Nrf2 and antioxidant enzymes expression were evaluated using western blotting analyses. We found that AGE promoted the accumulation of Nrf2 into the nucleus in a time- and dose-dependent manner and increased the gene expression and polypeptide level of heme oxygenase-1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM). Moreover, the effect of AGE in elevating the gene expression of HO-1 and GCLM was found to be mediated via Nrf2 activation in human umbilical vein endothelial cells. Taken together, these observations suggest that AGE induces the expression of HO-1 and GCLM, which are antioxidant enzymes, via activation of the Nrf2-ARE signaling pathway. [ABSTRACT FROM AUTHOR]

Aged garlic extract (AGE) produces neurotrophic effects on cultured fetal rat hippocampal neurons. These studies examined the molecular events triggered by AGE that might account for a suppression of neuronal cell death. Genes differentially expressed by the addition of AGE in primary cultured hippocampal neurons isolated from fetal rat brain were screened using mRNA differential display. Four cDNA clones were significantly enhanced at their transcriptional level; they were designated as #24, #110, #153 and #155. Quantitative reverse transcriptionpolymerase chain reaction (RT-PCR), as well as dot-blot hybridization combined with RT-PCR, confirmed that the transcription from these four genes was elevated at least twofold, particularly the mRNA of #153, which was increased >20 times 72 h after the addition of AGE. A homology search of the respective cDNA sequences in the DNA database revealed that #153 is an α2-microglobulin-related protein (α2MRP) gene. The others genes were not identified. Induction of the α2MRP gene expression occurred within 24 h after addition of AGE. These findings suggest a possible mechanism by which AGE may regulate gene expression and bring about a neurotrophic effect. Further, our results suggest that cx2MRP may function at the initial step of the molecular events triggered by AGE and play an important role in the survival of hippocampal neurons. [ABSTRACT FROM AUTHOR]