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Article: Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases.

Vallee, Kaylie-Anna Juliette / Fields, Jerel Adam

2022 Volume 12, Issue 3

Abstract: Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative ... ...

Abstract	Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative diseases due to their pro-inflammatory phenotype close association with damaged neurons. Thus, strategies to reduce astrocyte reactivity may support brain health. Caloric restriction and a ketogenic diet limit energy production via glycolysis and promote oxidative phosphorylation, which has gained traction as a strategy to improve brain health. However, it is unknown how caloric restriction affects astrocyte reactivity in the context of neuroinflammation. We investigated how a caloric restriction mimetic and glycolysis inhibitor, 2-deoxyglucose (2-DG), affects interleukin 1β-induced inflammatory gene expression in human astrocytes. Human astrocyte cultures were exposed to 2-DG or vehicle for 24 h and then to recombinant IL-1β for 6 or 24 h to analyze mRNA and protein expression, respectively. Gene expression levels of proinflammatory genes (complement component 3, IL-1β, IL6, and TNFα) were analyzed by real-time PCR, immunoblot, and immunohistochemistry. As expected, IL-1β induced elevated levels of proinflammatory genes. 2-DG reversed this effect at the mRNA and protein levels without inducing cytotoxicity. Collectively, these data suggest that inhibiting glycolysis in human astrocytes reduces IL-1β-induced reactivity. This finding may lead to novel therapeutic strategies to limit inflammation and enhance bioenergetics toward the goal of preventing and treating neurodegenerative diseases.
Language	English
Publishing date	2022-02-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci12030308
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Article ; Online: Publisher Correction: Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management.

Ellis, Ronald J / Marquine, María J / Kaul, Marcus / Fields, Jerel Adam / Schlachetzki, Johannes C M

Nature reviews. Neurology

2023 Volume 19, Issue 12, Page(s) 787

Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Published Erratum
ZDB-ID	2491514-2
ISSN	1759-4766 ; 1759-4758
ISSN (online)	1759-4766
ISSN	1759-4758
DOI	10.1038/s41582-023-00895-y
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Article ; Online: Mitochondrial DNA and Electron Transport Chain Protein Levels Are Altered in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy: A Pilot Study.

Boustani, Ali / Kulbe, Jacqueline R / Andalibi, Mohammadsobhan Sheikh / Pérez-Santiago, Josué / Mehta, Sanjay R / Ellis, Ronald J / Fields, Jerel Adam

International journal of molecular sciences

2024 Volume 25, Issue 9

Abstract: Distal sensory polyneuropathy (DSP) and distal neuropathic pain (DNP) remain significant challenges for older people with HIV (PWH), necessitating enhanced clinical attention. HIV and certain antiretroviral therapies (ARTs) can compromise mitochondrial ... ...

Abstract	Distal sensory polyneuropathy (DSP) and distal neuropathic pain (DNP) remain significant challenges for older people with HIV (PWH), necessitating enhanced clinical attention. HIV and certain antiretroviral therapies (ARTs) can compromise mitochondrial function and impact mitochondrial DNA (mtDNA) replication, which is linked to DSP in ART-treated PWH. This study investigated mtDNA, mitochondrial fission and fusion proteins, and mitochondrial electron transport chain protein changes in the dorsal root ganglions (DRGs) and sural nerves (SuNs) of 11 autopsied PWH. In antemortem standardized assessments, six had no or one sign of DSP, while five exhibited two or more DSP signs. Digital droplet polymerase chain reaction was used to measure mtDNA quantity and the common deletions in isolated DNA. We found lower mtDNA copy numbers in DSP+ donors. SuNs exhibited a higher proportion of mtDNA common deletion than DRGs in both groups. Mitochondrial electron transport chain (ETC) proteins were altered in the DRGs of DSP+ compared to DSP- donors, particularly Complex I. These findings suggest that reduced mtDNA quantity and increased common deletion abundance may contribute to DSP in PWH, indicating diminished mitochondrial activity in the sensory neurons. Accumulated ETC proteins in the DRG imply impaired mitochondrial transport to the sensory neuron's distal portion. Identifying molecules to safeguard mitochondrial integrity could aid in treating or preventing HIV-associated peripheral neuropathy.
MeSH term(s)	Humans ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Male ; HIV Infections/metabolism ; HIV Infections/virology ; HIV Infections/genetics ; Pilot Projects ; Female ; Middle Aged ; Aged ; Ganglia, Spinal/metabolism ; Ganglia, Spinal/virology ; Mitochondria/metabolism ; Mitochondria/genetics ; Electron Transport Chain Complex Proteins/metabolism ; Electron Transport Chain Complex Proteins/genetics ; Peripheral Nerves/metabolism ; Peripheral Nerves/virology ; Peripheral Nerves/pathology ; Adult ; Sural Nerve/metabolism ; Sural Nerve/pathology
Chemical Substances	DNA, Mitochondrial ; Electron Transport Chain Complex Proteins
Language	English
Publishing date	2024-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25094732
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Article ; Online: Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management.

Ellis, Ronald J / Marquine, María J / Kaul, Marcus / Fields, Jerel Adam / Schlachetzki, Johannes C M

Nature reviews. Neurology

2023 Volume 19, Issue 11, Page(s) 668–687

Abstract: People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the ... ...

Abstract	People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.
MeSH term(s)	Humans ; HIV Infections/complications ; HIV Infections/drug therapy ; Central Nervous System Diseases ; Cognitive Dysfunction/etiology ; Cognitive Dysfunction/therapy
Language	English
Publishing date	2023-10-10
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2491514-2
ISSN	1759-4766 ; 1759-4758
ISSN (online)	1759-4766
ISSN	1759-4758
DOI	10.1038/s41582-023-00879-y
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Article ; Online: Elevated Biomarkers of Inflammation and Vascular Dysfunction Are Associated with Distal Sensory Polyneuropathy in People with HIV.

Andalibi, Mohammadsobhan Sheikh / Fields, Jerel Adam / Iudicello, Jennifer E / Diaz, Monica M / Tang, Bin / Letendre, Scott L / Ellis, Ronald J

International journal of molecular sciences

2024 Volume 25, Issue 8

Abstract: Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies ... ...

Abstract	Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178-448) and 643 (502-839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42-21.00], and 15.16 [1.07-215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration.
MeSH term(s)	Humans ; Female ; Male ; HIV Infections/complications ; HIV Infections/blood ; HIV Infections/drug therapy ; Biomarkers/blood ; Middle Aged ; Adult ; Inflammation/blood ; Polyneuropathies/blood ; Polyneuropathies/etiology ; Cross-Sectional Studies ; Cytokines/blood
Chemical Substances	Biomarkers ; Cytokines
Language	English
Publishing date	2024-04-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25084245
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Article ; Online: HIV in the cART era and the mitochondrial: immune interface in the CNS.

Fields, Jerel Adam / Ellis, Ronald J

International review of neurobiology

2019 Volume 145, Page(s) 29–65

Abstract: HIV-associated neurocognitive disorders (HAND) persist in the era of effective combined antiretroviral therapy (cART). A large body of literature suggests that mitochondrial dysfunction is a prospective etiology of HAND in the cART era. While viral load ... ...

Abstract	HIV-associated neurocognitive disorders (HAND) persist in the era of effective combined antiretroviral therapy (cART). A large body of literature suggests that mitochondrial dysfunction is a prospective etiology of HAND in the cART era. While viral load is often suppressed and the immune system remains intact in HIV+ patients on cART, evidence suggests that the central nervous system (CNS) acts as a reservoir for virus and low-level expression of viral proteins, which interact with mitochondria. In particular, the HIV proteins glycoprotein 120, transactivator of transcription, viral protein R, and negative factor have each been linked to mitochondrial dysfunction in the brain. Moreover, cART drugs have also been shown to have detrimental effects on mitochondrial function. Here, we review the evidence generated from human studies, animal models, and in vitro models that support a role for HIV proteins and/or cART drugs in altered production of adenosine triphosphate, mitochondrial dynamics, mitophagy, calcium signaling and apoptosis, oxidative stress, mitochondrial biogenesis, and immunometabolism in the CNS. When insightful, evidence of HIV or cART-induced mitochondrial dysfunction in the peripheral nervous system or other cell types is discussed. Lastly, therapeutic approaches to targeting mitochondrial dysfunction have been summarized with the aim of guiding new investigations and providing hope that mitochondrial-based drugs may provide relief for those suffering with HAND.
MeSH term(s)	Animals ; Antiretroviral Therapy, Highly Active/adverse effects ; Central Nervous System/metabolism ; HIV Infections/metabolism ; HIV Infections/pathology ; Human Immunodeficiency Virus Proteins/metabolism ; Humans ; Immune System/metabolism ; Mitochondria/drug effects ; Mitochondria/pathology
Chemical Substances	Human Immunodeficiency Virus Proteins
Language	English
Publishing date	2019-05-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209876-3
ISSN	2162-5514 ; 0074-7742
ISSN (online)	2162-5514
ISSN	0074-7742
DOI	10.1016/bs.irn.2019.04.003
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Article ; Online: Correction: GP120 and tenofovir alafenamide alter cannabinoid receptor 1 expression in hippocampus of mice.

Kulbe, Jacqueline Renee / Le, Alexandra Anh / Mante, Michael / Florio, Jazmin / Laird, Anna Elizabeth / Swinton, Mary K / Rissman, Robert A / Fields, Jerel Adam

Journal of neurovirology

2024 Volume 30, Issue 1, Page(s) 101–102

Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1283265-0
ISSN	1538-2443 ; 1355-0284
ISSN (online)	1538-2443
ISSN	1355-0284
DOI	10.1007/s13365-023-01192-6
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Article: Nicotine, THC, and Dolutegravir Modulate E-Cigarette-Induced Changes in Addiction- and Inflammation-Associated Genes in Rat Brains and Astrocytes.

Kulbe, Jacqueline Renee / Nguyen, Lauren / Le, Alexandra Anh / Laird, Anna Elizabeth / Taffe, Michael A / Nguyen, Jacques D / Fields, Jerel Adam

Brain sciences

2023 Volume 13, Issue 11

Abstract: E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated ...

Abstract	E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated Cytoskeleton-Associated Protein (ARC) have a role in addiction, synaptic plasticity, inflammation, and neurodegeneration. This study showed that 10 days of exposure to e-cigarette vapor altered gene expression in the brains of 6-month-old, male, Sprague Dawley rats. Specifically, the e-cigarette solvent vapor propylene glycol (PG) downregulated EGR2 and ARC mRNA expression in frontal cortex, an effect which was reversed by nicotine (NIC) and THC, suggesting that PG could have a protective role against NIC and cannabis dependence. However, in vitro, PG upregulated EGR2 and ARC mRNA expression at 18 h in cultured C6 rat astrocytes suggesting that PG may have neuroinflammatory effects. PG-induced upregulation of EGR2 and ARC mRNA was reversed by NIC but not THC. The HIV antiretroviral DTG reversed the effect NIC had on decreasing PG-induced upregulation of EGR2, which is concerning because EGR2 has been implicated in HIV latency reversal, T-cell apoptosis, and neuroinflammation, a process that underlies the development of HIV-associated neurocognitive disorders.
Language	English
Publishing date	2023-11-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci13111556
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Article ; Online: GP120 and tenofovir alafenamide alter cannabinoid receptor 1 expression in hippocampus of mice.

Kulbe, Jacqueline Renee / Le, Alexandra Anh / Mante, Michael / Florio, Jazmin / Laird, Anna Elizabeth / Swinton, Mary K / Rissman, Robert A / Fields, Jerel Adam

Journal of neurovirology

2023 Volume 29, Issue 5, Page(s) 564–576

Abstract: Central nervous system (CNS) dysfunction remains prevalent in people with HIV (PWH) despite effective antiretroviral therapy (ART). There is evidence that low-level HIV infection and ART drugs may contribute to CNS damage in the brain of PWH with ... ...

Abstract	Central nervous system (CNS) dysfunction remains prevalent in people with HIV (PWH) despite effective antiretroviral therapy (ART). There is evidence that low-level HIV infection and ART drugs may contribute to CNS damage in the brain of PWH with suppressed viral loads. As cannabis is used at a higher rate in PWH compared to the general population, there is interest in understanding how HIV proteins and ART drugs interact with the endocannabinoid system (ECS) and inflammation in the CNS. Therefore, we investigated the effects of the HIV envelope protein gp120 and tenofovir alafenamide (TAF) on cannabinoid receptor 1 (CB
MeSH term(s)	Humans ; Mice ; Animals ; HIV Infections/drug therapy ; HIV Infections/genetics ; Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; HIV Envelope Protein gp120/genetics ; Adenine/pharmacology ; Mice, Transgenic ; Hippocampus ; Receptors, Cannabinoid/therapeutic use
Chemical Substances	Anti-HIV Agents ; HIV Envelope Protein gp120 ; Adenine (JAC85A2161) ; Receptors, Cannabinoid
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1283265-0
ISSN	1538-2443 ; 1355-0284
ISSN (online)	1538-2443
ISSN	1355-0284
DOI	10.1007/s13365-023-01155-x
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Article ; Online: Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder.

Canchi, Saranya / Swinton, Mary K / Rissman, Robert A / Fields, Jerel Adam

Journal of neuroinflammation

2020 Volume 17, Issue 1, Page(s) 112

Abstract: Background: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well ... ...

Abstract	Background: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era. Methods: In this study, using 33 postmortem frontal cortex (FC) tissues, neuropathological, molecular, and biochemical analyses were used to determine cellular localization and validate expression levels of the prolific transcription factor (TF), CCAAT enhancer binding protein (C/EBP) β, in brain tissues from HIV+ cognitively normal and HAND cases. RNA sequencing (seq) and transcriptomic analyses were performed on FC tissues including 24 specimens from well-characterized people with HIV that had undergone neurocognitive assessments. In vitro models for brain cells were used to investigate the role of C/EBPβ in mediating gene expression. Results: The most robust signal for TF dysregulation was observed in cases diagnosed with minor neurocognitive disorder (MND) compared to cognitive normal (CN) cases. Of particular interest, due to its role in inflammation, autophagy and neurogenesis, C/EBPβ was significantly upregulated in MND compared to CN brains. C/EBPβ was increased at the protein level in HAND brains. C/EBPβ levels were significantly reduced in neurons and increased in astroglia in HAND brains compared to CN. Transfection of human astroglial cells with a plasmid expressing C/EBPβ induced expression of multiple targets identified in the transcriptomic analysis of HAND brains, including dynamin-1-like protein (DNM1L) and interleukin-1 receptor-associated kinase 1. Recombinant HIV-Tat reduced and increased C/EBPβ levels in neuronal and astroglial cells, respectively. Conclusions: These findings are the first to present RNAseq-based transcriptomic analyses of HIV+ brain tissues, providing further evidence of altered neuroinflammation, neurogenesis, mitochondrial function, and autophagy in HAND. Interestingly, these studies confirm a role for CEBPβ in regulating inflammation, metabolism, and autophagy in astroglia. Therapeutic strategies aimed at transcriptional regulation of astroglia or downstream pathways may provide relief to HIV+ patients at risk for HAND and other neurological disorders.
MeSH term(s)	AIDS Dementia Complex/metabolism ; Adult ; Brain/metabolism ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; Female ; Gene Expression Profiling ; Humans ; Male
Chemical Substances	CCAAT-Enhancer-Binding Protein-beta ; CEBPB protein, human
Language	English
Publishing date	2020-04-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-020-01781-w
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