HIV infection of the central nervous system leads to HIV-associated dementia (HAD) in a substantial subset of infected individuals. The pathogenesis of neuronal dysfunction in HAD is not well understood, but previous studies have demonstrated evidence for activation of apoptotic pathways. The tumor suppressor transcription factor p53 is an apical mediator of neuronal apoptosis following a variety of injurious stimuli. To determine whether p53 participates in HAD, we exposed cerebrocortical cultures from wild-type and p53 deficient mice to the neurotoxic HIV envelope protein gp120. Using neuron/microglia co-culture of mixed p53 genotype, we observed that both neurons and microglia require p53 for gp120 induced neuronal apoptosis. Additionally, accumulation of p53 protein in neurons was recently reported in post-mortem cortical tissue from a small group of HAD patients. Using a much larger cohort of HAD cases, we extend this finding and report that p53 protein also increases in non-neuronal cells, including microglia. Taken together these findings demonstrate a novel role for p53 in the microglial response to gp120. Additionally, these findings, in conjunction with a recent report that monocytes expressing HIV-Tat also secrete neurotoxins that promote p53 activation, suggest that distinct HIV proteins may converge on the p53 pathway to promote neurotoxicity.

The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to multiple forms of cellular stress. p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from animal models and patients with chronic neurodegenerative diseases. p53 deficiency or p53 inhibition protects neurons from a wide variety of acute toxic insults. Signal transduction pathways associated with p53-induced neuronal cell death are being characterized, suggesting that intervention may prove effective in maintaining neuronal viability and restoring function following neural injury and disease.

AimThe purpose of this study was to investigate the possible mechanisms of genistein (GEN) and daidzein (DAI) in inducing apoptosis of colon cancer cells by inhibition of lipid droplets (LDs) accumulation.MethodsHT-29 cells were used and treated by GEN or DAI in this paper. LDs accumulation was induced and inhibited by oleic acid (OA) and C75, respectively. The expression changes of LDs-related markers were confirmed by semiquantitative real time-PCR (RT–PCR), Western blotting, and immunofluorescence staining.ResultsGEN and DAI effectively reduced the LDs accumulation and downregulated the expression of Perilipin-1, ADRP and Tip-47 family proteins and vimentin levels. GEN and DAI significantly induced the mRNA expression of PPAR-γ, Fas, FABP, glycerol-3-phosphate acyltransferase (GPAT3), and microsomal TG transfer protein (MTTP), and reduced the mRNA expression of UCP2. Furthermore, the results showed a decrease of PI3K expression by GEN and DAI when compared with OA treatment, and both GEN and DAI can increase the expression of FOXO3a and caspase-8 significantly when these proteins were decreased by OA treatment. GEN is more effective than DAI in inducing cell apoptosis.ConclusionOur results demonstrated that GEN and DAI inhibit the accumulation of LDs by regulating LDs-related factors and lead to a final apoptosis of colon cancer cells. These results may provide important new insights into the possible molecular mechanisms of isoflavones in anti-obesity and anti-tumor functions.

Cultured cortical neurons exposed to the Human Immunodeficiency Virus gp120 coat protein undergo apoptosis involving activation of both caspase-8 and caspase-9. Additionally, gp120-mediated neuronal apoptosis requires the pro-apoptotic transcription factor p53. As caspase-8-induced apoptosis does not typically require p53, we examined the possibility of a novel role for p53 in caspase-8 activation initiated by gp120. We observed that gp120 treatment of cultured cortical neurons induced caspase-8 activity and Bid cleavage independently of p53, but induction of caspase-3 enzymatic activity required p53 expression. These findings suggested the possibility that p53 down-regulates a caspase-3 inhibitor. We observed high-level expression of the caspase-3/9 inhibitor X-linked inhibitor of apoptosis protein (XIAP) in cultured cortical neurons. Adenoviral expression of p53 or induction of endogenous p53 by camptothecin treatment reduced XIAP protein in neurons. Infection with a p53 expressing adenovirus increased expression of the mRNA for Omi/HtrA2, a protease that cleaves and inactivates XIAP. These findings suggest that p53 regulates neuronal apoptosis, in part, by suppressing the anti-apoptotic protein XIAP via transcriptional activation of Omi/HtrA2.