Soy Isoflavones Genistein and Daidzein Exert Anti-Apoptotic Actions via a Selective ER-mediated Mechanism in Neurons following HIV-1 Tat1–86 Exposure

HIV-1 viral protein Tat partially mediates the neural dysfunction and neuronal cell death associated with HIV-1 induced neurodegeneration and neurocognitive disorders. Soy isoflavones provide protection against various neurotoxic insults to maintain neuronal function and thus help preserve neurocognitive capacity.We demonstrate in primary cortical cell cultures that 17β-estradiol or isoflavones (genistein or daidzein) attenuate Tat(1-86)-induced expression of apoptotic proteins and subsequent cell death. Exposure of cultured neurons to the estrogen receptor antagonist ICI 182,780 abolished the anti-apoptotic actions of isoflavones. Use of ERα or ERβ specific antagonists determined the involvement of both ER isoforms in genistein and daidzein inhibition of caspase activity; ERβ selectively mediated downregulation of mitochondrial pro-apoptotic protein Bax. The findings suggest soy isoflavones effectively diminished HIV-1 Tat-induced apoptotic signaling.Collectively, our results suggest that soy isoflavones represent an adjunctive therapeutic option with combination anti-retroviral therapy (cART) to preserve neuronal functioning and sustain neurocognitive abilities of HIV-1 infected persons

Protein oxidation and enzyme activity decline in old brown Norway rats are reduced by dietary restriction. Mech Ageing Dev

Abstract The effect of aging and diet restriction (DR) on the activity of creatine kinase (CK), glutamine synthetase (GS) and protein carbonyl formation in the cerebellum, hippocampus and cortex of male and female brown Norway (BN) rats has been investigated. It was demonstrated that CK activity in three different regions of the rat brain declines with age by 30%. Age-related decrease of GS activity was only 10 -13% and did not reach statistical significance. Consistent with previously published studies, age-related increase of protein carbonyl content in each brain area studied has been observed. Preventive effects of a caloric restricted diet on the age-associated protein oxidation and changes of the activity of CK and GS in the brain was observed for both aging male and female BN rats. DR delayed the accumulation of protein carbonyls. Age-related changes of CK activity in rat brain were abrogated by DR. The activity of GS in the brain of old rats subjected to the caloric restricted diet was higher than that in the brain of young animals fed ad libitum. The results are consistent with the notion that DR may relieve age-associated level of oxidative stress and lessen protein damage. © 1998 Elsevier Science Ireland Ltd. 100 (1998) 157-168 15

Soy isoflavones genistein and daidzein protect primary cortical cultures from Tat neurotoxicity.

<p>Primary cortical neurons were exposed to estrogen (0.1, 2.0 and 10 nM), or isoflavones (0.05, 0.2 and 1 µM) 24 hr prior to the start of Tat_1–86 B (50 nM) treatment. Cell viability was assessed by Live/Dead assay. Live/Dead ratios were determined after 48 hr (<b>A-C</b>) or 5 days (<b>D-F</b>) of the continuous exposure to Tat or equal volume of vehicle in cell culture groups that were treated or not treated with estrogen, GEN, or DAI. Data represents mean values ± SEM, n of cultures analyzed  = 7–12 per each group. *- indicates significant (<i>p</i>≤0.05) protective effects of the selected compounds against Tat neurotoxicity (cell viability decrease) in cortical cell cultures. Repeated (2–3) trials using cell culture preparations from different litters were carried out to ensure the reproducibility of the results.</p

Genistein and daidzein attenuate Tat-induced caspase activation in primary cortical cultures.

<p>Cortical cultures were treated with 1 µM GEN or DAI 24 hr prior to Tat exposure. Expression of activated apoptotic proteins <b>A</b>. Caspase 9 (4 hr of Tat exposure) and <b>B</b>. caspase 3 (4 hr Tat exposure) was assessed by ELISA experiments. Data represents mean values ± SEM, with experiments performed in triplicate, *<i>p≤</i>0.05 as compared to Tat-treated cultures.</p

ER subtype specific effects against caspase activity and Bax expression.

<p>Similar to 17β-estradiol (<b>A</b>), GEN (<b>B</b>) and DAI (<b>C</b>) effects against Tat-induced caspase 3 activity were maintained in the presence of specific antagonists for ERα (MPP) and ERβ (PHTPP). ER subtype antagonists reveal that ERβ signaling was preferential for GEN (<b>E</b>) effects on Bax. DAI (<b>F</b>) effects on Bax were blocked in the presence of both ER subtype antagonists. Data represents mean values ± SEM, *<i>p≤</i>0.05 as compared to GEN/DAI+Tat treated cultures.</p

Estrogen receptors mediate isoflavone effects on Caspase 3 and Bax expression following Tat exposure.

<p><b>A</b>. GEN or DAI effects on caspase 3 expression were blocked in the presence of ER antagonist, ICI 182,780. <b>B</b>. GEN or DAI effects on Tat-induced expression of Bax were reversed by ICI 182,780, suggesting that estrogenic actions on caspase 3 and Bax are ER mediated. Data represents mean values ± SEM, *<i>p≤</i>0.05 vs. GEN/DAI+T treated cultures.</p