Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway

Li, Juan; Wang, Wenguang; Tong, Pinfen; Leung, Chi‐Kwan; Yang, Genmeng; Li, Zhen; Li, Na; Sun, Xiaomei; Han, Yuanyuan; Lü, Caixia; Kuang, Dexuan; Dai, Jiejie; Zeng, Xiaofeng

doi:10.3389/fnins.2018.00921

Cited by 17 publications

(10 citation statements)

References 77 publications

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“…On the other hand, defective autophagy promotes apoptosis and accelerated senescence [6]. Our results showed that autophagy promotes EPC cell migration, adherent ability, angiogenic ability, and cell viability, which is consistent with previous studies [45, 46]. In our senescence experiments, we found MeCP2 levels increased but FoxO3a levels decreased.…”

Section: Discussionsupporting

confidence: 92%

MeCP2 inhibits cell functionality through FoxO3a and autophagy in endothelial progenitor cells

Zha

Chen

et al. 2019

Aging

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Objectives: Autophagy is an evolutionarily conserved intracellular degradation mechanism in which cell constituents are phagocytosed to maintain cellular homeostasis. Forkhead box O 3a (FoxO3a) promotes autophagy to protect cells from environmental stress. Methylated CpG binding protein 2 (MeCP2) is a nuclear protein that binds DNA and represses transcription. However, the mechanism and interplay between FoxO3a and MeCP2 underlying endothelial progenitor cell (EPC) function are not fully understood.Results: In EPCs, MeCP2 overexpression attenuated autophagy and cell functionality, which were reversed by the autophagy activator rapamycin or co-transfection with FoxO3a. FoxO3a promoted cell function, which was reversed by the autophagy inhibitor chloroquine. Following MeCP2 overexpression, MeCP2 was found enriched on the FoxO3a promoter, resulting in promoter hypermethylation and enhanced H3K9 histone modification in nucleosomes of the FoxO3a promoter.Conclusions: MeCP2 attenuated cell functionality via DNA hypermethylation and histone modification of the FoxO3a promoter to inhibit FoxO3a transcription and autophagy.Materials and Methods: EPCs were isolated from human umbilical cord blood and treated with adenoviral vectors containing interference sequences. The effects and mechanism of MeCP2 and FoxO3a were analyzed by utilizing western blotting, cell counting kit-8, transwell plates, Matrigel, matrix adhesion, transmission electron microscopy, and chromatin immunoprecipitation.

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Section: Discussionsupporting

confidence: 92%

MeCP2 inhibits cell functionality through FoxO3a and autophagy in endothelial progenitor cells

Zha

Chen

et al. 2019

Aging

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“…For example, deficits and mutations in eIF2 and eIF4 pathways have been associated with neurological disorders and aging [96,97]. The fact that these pathways are deeply affected by Meth, and their recovery in the presence of Tat, suggests the potential involvement of upstream mTOR [98][99][100][101][102] as a critical element in Tat along with Meth sensitization, and as a response to mitochondrial oxidative stress [103,104]. In the presence of Tat, mitochondrial dysfunction and oxidative phosphorylation pathways were also maintained at control levels.…”

Section: Discussionmentioning

confidence: 99%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

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Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

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“…Compared with rodents, the tree shrew, a novel model animal, has a more developed brain and is more similar to humans in anatomy, physiology, and genomics ( Fan et al, 2013 ). Recently, the tree shrews have been used as experimental animals in some studies related to METH addiction and toxicity ( Li et al, 2018a ; Huang et al, 2020 ). Thus, the human brain microvascular endothelial cell line hCMEC/D3 and tree shrews are used as the research objects for in vivo and in vitro analyses of how METH and HIV-Tat co-induce oxidative stress injury to damage the BBB, and to identify the TRPM2 channel’s function and mechanism in this process.…”

Section: Introductionmentioning

confidence: 99%

“…Mediouni et al (Mediouni et al, 2015) believe that METH abuse can enhance the neurotoxicity of HIV-Tat, and their combined effects can lead to neurotransmitter metabolism disorder, oxidative stress response, and neuroinflammation. Other studies have shown that METH and HIV-Tat can co-induce autophagy and apoptosis of nerve cells (Qi et al, 2011;Li et al, 2018a;Zeng et al, 2018). To become toxic in the CNS, METH, and HIV must first break through the blood-brain barrier (BBB).…”

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confidence: 99%

Methamphetamine and HIV-Tat Protein Synergistically Induce Oxidative Stress and Blood-Brain Barrier Damage via Transient Receptor Potential Melastatin 2 Channel

et al. 2021

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Synergistic impairment of the blood-brain barrier (BBB) induced by methamphetamine (METH) and HIV-Tat protein increases the risk of HIV-associated neurocognitive disorders (HAND) in HIV-positive METH abusers. Studies have shown that oxidative stress plays a vital role in METH- and HIV-Tat-induced damage to the BBB but have not clarified the mechanism. This study uses the human brain microvascular endothelial cell line hCMEC/D3 and tree shrews to investigate whether the transient receptor potential melastatin 2 (TRPM2) channel, a cellular effector of the oxidative stress, might regulate synergistic damage to the BBB caused by METH and HIV-Tat. We showed that METH and HIV-Tat damaged the BBB in vitro, producing abnormal cell morphology, increased apoptosis, reduced protein expression of the tight junctions (TJ) including Junctional adhesion molecule A (JAMA) and Occludin, and a junctional associated protein Zonula occludens 1 (ZO1), and increased the flux of sodium fluorescein (NaF) across the hCMEC/D3 cells monolayer. METH and HIV-Tat co-induced the oxidative stress response, reducing catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) activity, as well as increased reactive oxygen species (ROS) and malonaldehyde (MDA) level. Pretreatment with n-acetylcysteine amide (NACA) alleviated the oxidative stress response and BBB damage characterized by improving cell morphology, viability, apoptosis levels, TJ protein expression levels, and NaF flux. METH and HIV-Tat co-induced the activation and high protein expression of the TRPM2 channel, however, early intervention using 8-Bromoadenosine-5′-O-diphosphoribose (8-Br-ADPR), an inhibitor of TPRM2 channel, or TRPM2 gene knockdown attenuated the BBB damage. Oxidative stress inhibition reduced the activation and high protein expression of the TRPM2 channel in the in vitro model, which in turn reduced the oxidative stress response. Further, 8-Br-ADPR attenuated the effects of METH and HIV-Tat on the BBB in tree shrews—namely, down-regulated TJ protein expression and increased BBB permeability to Evans blue (EB) and NaF. In summary, the TRPM2 channel can regulate METH- and HIV-Tat-induced oxidative stress and BBB injury, giving the channel potential for developing drug interventions to reduce BBB injury and neuropsychiatric symptoms in HIV-infected METH abusers.

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Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway

Cited by 17 publications

References 77 publications

MeCP2 inhibits cell functionality through FoxO3a and autophagy in endothelial progenitor cells

MeCP2 inhibits cell functionality through FoxO3a and autophagy in endothelial progenitor cells

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Methamphetamine and HIV-Tat Protein Synergistically Induce Oxidative Stress and Blood-Brain Barrier Damage via Transient Receptor Potential Melastatin 2 Channel

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