Dataset Information

HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

ABSTRACT: Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined. Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 ?M) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses. This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner. In sum, targeted therapeutic intervention with SE may prevent HIV-1 + drug abuse synaptopathy, and thereby potentially influence the development of HAND.

SUBMITTER: Bertrand SJ

PROVIDER: S-EPMC4561964 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

Bertrand Sarah J SJ Hu Calvin C Aksenova Marina V MV Mactutus Charles F CF Booze Rosemarie M RM

Frontiers in microbiology 20150908

Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol ( ...[more]

PMID: 26441850

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Project description:IntroductionMitochondrial dysregulation is a key event in HIV-1 infection. Recent studies have suggested that age-related neurodegenerative disorders are associated with increased mitochondrial DNA (mtDNA) damage. As accelerated ageing was found in HIV-1 patients, we hypothesized that HIV-1 infection or HIV-1 proteins can lead to mtDNA damage. Unrepaired mtDNA impairs mitochondrial function, which can lead to oxidative stress and cell death. Investigations of mechanisms of mtDNA damage are limited by the lack of available human models.MethodsWe compared mtDNA or nDNA (nuclear DNA) damage in human cortical neurons and PBMC cells. Primary neuronal cultures were incubated with conditioned media from HIV-1 infected PBMC, or HIV-1 viral proteins Tat or Vpr. Total genomic DNA (nuclear and mtDNA) was isolated using the QIAamp Kit. Nuclear and mtDNA were amplified using the long q-PCR/Gene Amp XL Kit. Real-Time RT-PCR using mitochondrial energy metabolism array was performed to assess mitochondrial energy metabolism markers. Superoxide dismutase (SOD) activity in neuronal cells was measured by the OxiSelect SOD Activity Assay. Reactive oxygen species (ROS) were determined by the confocal microscopy. ATP levels were analyzed using ATP determination biochemical assay. Mitochondrial, cytoplasmic and nuclear proteins were studied by quantitative western-blot assay.ResultsWe show that both treatment of neuronal cells with HIV-1 conditioned media, or infection of PBMC with HIV-1 increase mtDNA damage in cells. mtDNA damage was also seen in neuronal cells, incubated with HIV-1 proteins, Tat and Vpr. Next, we confirmed that mtDNA damage was also increased in neuronal cells transfected by Tat expressing plasmids. We showed that mtDNA was not damaged in neuronal cells following treatment with heat inactivated HIV-1 or Tat protein. Further, we demonstrated that HIV-1 or Tat caused more mtDNA damage compared to nuclear DNA damage in neuronal cells. Finally, we showed that Tat dysregulates RNA expression of several genes regulating mitochondrial energy metabolism, suggesting involvement of Tat in mitochondrial bioenergetics in human neurons. Finally, our hypothesis was confirmed by qWestern analysis of mitochondrial and apoptotic proteins demonstrating the accumulation of apoptotic Bax and Bad proteins in mitochondrial fraction of Tat-treated neuronal cells, suggesting toxic effects of Tat on mitochondrial survival.ConclusionWe showed an increase of mtDNA damage in primary neurons, treated with HIV-1 proteins and in PBMC, infected with HIV-1. Increased mtDNA damage can lead to neurodegeneration, and cause neuronal apoptosis. Our system presents a suitable model to study mtDNA changes during HIV-1 infection.

Project description:S-(-)equol, an intestinally derived metabolite of the soy isoflavone daidzein, is proposed to enhance the efficacy of soy diets. Adults differ in their ability to produce equol when consuming soy foods for reasons that remain unclear. Therefore, we performed a comprehensive dietary analysis of 143 macro- and micronutrients in 159 healthy adults in the United States (n = 89) and Australia (n = 70) to determine whether the intake of specific nutrients favors equol production. Three-d diet records were collected and analyzed using Nutrition Data System for Research software and S-(-)equol was measured in urine by mass spectrometry. Additionally, in a subset of equol producers and nonproducers (n = 10/group), we examined the long-term stability of equol producer status by retesting 12, 18, and 24 mo later. Finally, the effect of oral administration of the antibiotic metronidazole (500 mg/d for 7 d) on equol production was examined in 5 adults monitored during a 4-mo follow-up period. Equol producers accounted for 30.3% and 28.6% of the United States and Australian participants, respectively (overall frequency, 29.6%). No significant differences were observed for total protein, carbohydrate, fat, saturated fat, or fiber intakes between equol producers and nonproducers. However, principal component analysis revealed differences in several nutrients, including higher intakes of polyunsaturated fatty acids (P = 0.039), maltose (P = 0.02), and vitamins A (P = 0.01) and E (P = 0.035) and a lower intake of total cholesterol (P = 0.010) in equol producers. During a 2-y period, equol producer status remained unchanged in all nonproducers and in 80% of equol producers, whereas metronidazole abolished equol production in only 20% of participants. In conclusion, these findings suggest that major differences in the macronutrient content of the diet appear not to influence equol production, but subtle differences in some nutrients may influence the ability to produce equol, which was a relatively stable phenomenon.

Dataset Information

HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

Publications

HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

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