Genistein, a soy isoflavone, up‐regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NFκB

Abstract

We have previously reported that estrogens up-regulate longevity-associated genes. As recent evidence has shown that estrogen replacement therapy is associated with an increased risk of cardiovascular disease, we have studied the effects of genistein, a soy isoflavone with a similar structure to estradiol, on the expression of antioxidant, longevity-related genes. MCF-7 cells (human mammary gland tumor cell line) were incubated for 48 h with 0.5 microM genistein, a concentration found in the plasma of populations consuming diets rich in soy protein. Peroxide levels were determined by fluorimetry, activation of extracellular-signal regulated kinase (ERK1/2), and nuclear factor kappaB (NFkappaB)-signaling pathways by Western blot analysis and ELISA, respectively, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Inhibition of basal peroxide levels in MCF-7 cells by genistein was prevented by pretreatment of cells with the estrogen receptor antagonist tamoxifen. Phosphorylation of extracellular regulated kinase (ERK)1/2 led to an activation of NFkappaB, as indicated by increased p50 subunit expression in nuclear extracts, and increased mRNA levels of the antioxidant enzyme manganese-superoxide dismutase (MnSOD). Inhibition of ERK1/2 abrogated genistein-mediated NFkappaB activation and elevated expression of MnSOD. Our molecular studies may provide a basis to determine the effects of genistein and other soy protein-derived products on longevity in both animals and the human population.

Therapeutic Potential of Mesenchymal Stem Cells vs. Estradiol Benzoate or Avosoya on the Cerebellar Cortex of Ovariectomized Adult Albino Rats

“…Moreover, phytoestrogens have the advantage of treating both men and women and they do not show any significant feminizing effects. Limited effects on cardiovascular system or on the promotion of cancer have been reported [51].…”

“…Genistein (the major phytoestrogen present in soy), prevents both mitochondrial peroxide production and cytochrome c liberation. Therefore, phytoestrogens mimic the action of estrogen, but they do not have their side effects [51]. This protective effect may come from the stimulation of Erβ, which activates the estrogen response element of the Bcl-2 gene, and then increases transcription and translation to up regulate the expression of Bcl-2 [35].…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…133,134 Genistein has been shown to improve endothelial function and upregulate antioxidant genes through ERK1/2 and NFB signaling pathways, both properties that may be beneficial for cardiovascular health. 135,136 In a recent study, genistein mimicked the actions of 17␤-estradiol in its ability to localize phospho-Akt to the nucleus in cultured cardiac myocytes, a potentially cardioprotective outcome. 75 It is unclear whether the mechanism of this cardioprotection by genistein is mediated through ERs or through some other mechanism.…”

Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats

“…Genistein may have a beneficial influence similar to that of oestrogen but without the negative side effects (Bang et al, 2004). Genistein acts via oestrogen receptors to stimulate MAP kinases; these proteins activate the NFĸB signaling pathway and thereby induce overexpression of manganese superoxide dismutase (MnSOD), which serves as antioxidant in the cell (Akiyama et al, 1987;Borras et al, 2006). Recently, Huang and Zhang (Huang and Zhang, 2010) observed that chronic ingestion of genistein reduced neuronal apoptosis in the brain of ovariectomized rats.…”