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Severtsev VV, Pavkina MA, Ivanets NN, Vinnikova MA, Yakovlev AA. Extracellular Vesicles as Potential Biomarkers in Addictive Disorders. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:1970-1984. [PMID: 39647826 DOI: 10.1134/s0006297924110117] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/03/2024] [Accepted: 08/09/2024] [Indexed: 12/10/2024]
Abstract
Small extracellular vesicles (sEVs) and their role in mental and addictive disorders are extremely promising research areas. Because of their small size, sEVs can pass through the blood-brain barrier. The membrane of sEVs contain proteins that protect them against destruction by the organism's immune system. Due to these properties, sEVs circulating in the blood can be used as potential biomarkers of processes occurring in the brain. Exposure to psychoactive substances in vitro and in vivo affects sEV biogenesis and significantly alters the amount of sEVs and chemical composition of their cargo. Based on the published reports, sEVs carry numerous potential biomarkers of addictive pathologies, although the diagnostic significance of these markers still has to be evaluated. A large body of evidence indicates that psychoactive substances influence Rab family GTPases, Toll-like receptors, complement system components, and cytokines. In some studies, the effect of psychoactive substances on sEVs was found to be sex-dependent. It has become commonly accepted that sEVs are involved in the regulation of neuroinflammation and interaction between glial cells and neurons, as well as between peripheral cells and cells of the central nervous system. Here, we formulated a hypothesis on the existence of two mechanisms/stages involved in the effect of psychoactive substances on sEVs: the "fast" mechanism that provides neuroplasticity, and the "slow" one, resulting from the impaired biogenesis of sEVs and formation of aberrant vesicles.
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Affiliation(s)
- Vsevolod V Severtsev
- Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119048, Russia.
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical-Biological Agency of the Russian Federation, Moscow, 143007, Russia
| | - Margarita A Pavkina
- Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119048, Russia
| | - Nikolay N Ivanets
- Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119048, Russia
| | - Maria A Vinnikova
- Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119048, Russia
- Moscow Scientific and Practical Center of Narcology, Moscow Healthcare Department, Moscow, 109390, Russia
| | - Alexander A Yakovlev
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, 117485, Russia
- Research and Clinical Center for Neuropsychiatry, Moscow Healthcare Department, Moscow, 115419, Russia
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Kumar A, Nader MA, Deep G. Emergence of Extracellular Vesicles as "Liquid Biopsy" for Neurological Disorders: Boom or Bust. Pharmacol Rev 2024; 76:199-227. [PMID: 38351075 PMCID: PMC10877757 DOI: 10.1124/pharmrev.122.000788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 11/11/2023] [Accepted: 11/27/2023] [Indexed: 02/16/2024] Open
Abstract
Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases and disorders. The feasibility of enriching specific subpopulations of EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight from various tissues and organs, including the brain. Over the past decade, EVs in bodily fluids have been extensively studied for biomarkers associated with various neurological disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorders, substance use disorders, human immunodeficiency virus-associated neurocognitive disorder, and cancer/treatment-induced neurodegeneration. These studies have focused on the isolation and cargo characterization of either total EVs or brain cells, such as neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, and endothelial-derived EVs from biofluids to achieve early diagnosis and molecular characterization and to predict the treatment and intervention outcomes. The findings of these studies have demonstrated that EVs could serve as a repetitive and less invasive source of valuable molecular information for these neurological disorders, supplementing existing costly neuroimaging techniques and relatively invasive measures, like lumbar puncture. However, the initial excitement surrounding blood-based biomarkers for brain-related diseases has been tempered by challenges, such as lack of central nervous system specificity in EV markers, lengthy protocols, and the absence of standardized procedures for biological sample collection, EV isolation, and characterization. Nevertheless, with rapid advancements in the EV field, supported by improved isolation methods and sensitive assays for cargo characterization, brain cell-derived EVs continue to offer unparallel opportunities with significant translational implications for various neurological disorders. SIGNIFICANCE STATEMENT: Extracellular vesicles present a less invasive liquid biopsy approach in the diagnosis and prognosis of various neurological disorders. Characterizing these vesicles in biofluids holds the potential to yield valuable molecular information, thereby significantly impacting the development of novel biomarkers for various neurological disorders. This paper has reviewed the methodology employed to isolate extracellular vesicles derived from various brain cells in biofluids, their utility in enhancing the molecular understanding of neurodegeneration, and the potential challenges in this research field.
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Affiliation(s)
- Ashish Kumar
- Departments of Cancer Biology (A.K., G.D.), Physiology and Pharmacology (M.A.N.), Radiology (M.A.N.), and Center for Addiction Research (M.A.N., G.D.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina (G.D.); and Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina (G.D.)
| | - Michael A Nader
- Departments of Cancer Biology (A.K., G.D.), Physiology and Pharmacology (M.A.N.), Radiology (M.A.N.), and Center for Addiction Research (M.A.N., G.D.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina (G.D.); and Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina (G.D.)
| | - Gagan Deep
- Departments of Cancer Biology (A.K., G.D.), Physiology and Pharmacology (M.A.N.), Radiology (M.A.N.), and Center for Addiction Research (M.A.N., G.D.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina (G.D.); and Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina (G.D.)
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Zhu J, Chen Y, Ji J, Wang L, Xie G, Tang Z, Qu X, Liu Z, Ren G. Microglial exosomal miR-466i-5p induces brain injury via promoting hippocampal neuron apoptosis in heatstroke. Front Immunol 2022; 13:968520. [PMID: 36311808 PMCID: PMC9597693 DOI: 10.3389/fimmu.2022.968520] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/22/2022] [Indexed: 11/19/2022] Open
Abstract
Background Brain injury is the main cause of poor prognosis in heatstroke (HS) patients due to heat-stress-induced neuronal apoptosis. However, as a new cross-talk way among cells, whether microglial exosomal-microRNAs (miRNAs) are involved in HS-induced neuron apoptosis has not been elucidated. Methods We established a heatstroke mouse model and a heat-stressed neuronal cellular model on HT22 cell line. Then, we detected neuron apoptosis by histopathology and flow cytometry. The microglial exosomes are isolated by standard differential ultracentrifugation and characterized. Recipient neurons are treated with the control and HS exosomes, whereas in vivo, the exosomes were injected into the mice tail vein. The internalization of HS microglial exosomes by neurons was tracked. Apoptosis of HT22 was evaluated by flow cytometry and Western blot in vitro, TUNEL assay, and immunohistochemistry in vivo. We screened miR-466i-5p as the mostly upregulated microRNAs in HS exosomes by high-throughput sequencing and further conducted gene ontology (GO) pathway analysis. The effect and mechanism of HS exosomal miR-466i-5p on the induction of neuron apoptosis are demonstrated by nasal delivery of miR-466i-5p antagomir in vivo and transfecting miR-466i-5p mimics to HT22 in vitro. Results HS induced an increase in neurons apoptosis. Microglial exosomes are identified and taken up by neurons, which induced HT22 apoptosis in vivo and vitro. HS significantly changed the miRNA profiles of microglial exosomes based on high-throughput sequencing. We selected miR-466i-5p as a target, and upregulated miR-466i-5p induced neurons apoptosis in vivo and vitro experiments. The effects are exerted by targeting Bcl-2, activating caspase-3 to induce neurons apoptosis. Conclusions We demonstrate the effect of microglial exosomal miR-466i-5p on neurons apoptosis and reveal potentially Bcl-2/caspase-3 pathway in heatstroke.
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Affiliation(s)
- Jie Zhu
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
| | - Yahong Chen
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
| | - Jingjing Ji
- Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, China
- Guangdong Branch Center, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Guangzhou, China
| | - Longyan Wang
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
| | - Guoqiang Xie
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
| | - Zhen Tang
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
| | - Xiangmeng Qu
- Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province, School of Biomedical Engineering, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Guangli Ren, ; Zhifeng Liu, ; Xiangmeng Qu,
| | - Zhifeng Liu
- Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, China
- Guangdong Branch Center, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Guangzhou, China
- *Correspondence: Guangli Ren, ; Zhifeng Liu, ; Xiangmeng Qu,
| | - Guangli Ren
- Department of Pediatric, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, China
- *Correspondence: Guangli Ren, ; Zhifeng Liu, ; Xiangmeng Qu,
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Gabrielli M, Raffaele S, Fumagalli M, Verderio C. The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after? Front Cell Neurosci 2022; 16:984690. [PMID: 36176630 PMCID: PMC9514840 DOI: 10.3389/fncel.2022.984690] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/23/2022] [Indexed: 11/30/2022] Open
Abstract
As resident component of the innate immunity in the central nervous system (CNS), microglia are key players in pathology. However, they also exert fundamental roles in brain development and homeostasis maintenance. They are extremely sensitive and plastic, as they assiduously monitor the environment, adapting their function in response to stimuli. On consequence, microglia may be defined a heterogeneous community of cells in a dynamic equilibrium. Extracellular vesicles (EVs) released by microglia mirror the dynamic nature of their donor cells, exerting important and versatile functions in the CNS as unbounded conveyors of bioactive signals. In this review, we summarize the current knowledge on EVs released by microglia, highlighting their heterogeneous properties and multifaceted effects.
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Affiliation(s)
- Martina Gabrielli
- CNR Institute of Neuroscience, Vedano al Lambro, Italy
- *Correspondence: Martina Gabrielli,
| | - Stefano Raffaele
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Marta Fumagalli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Claudia Verderio
- CNR Institute of Neuroscience, Vedano al Lambro, Italy
- Claudia Verderio,
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Barreto BR, D’Acunzo P, Ungania JM, Das S, Hashim A, Goulbourne CN, Canals-Baker S, Saito M, Saito M, Sershen H, Levy E. Cocaine Modulates the Neuronal Endosomal System and Extracellular Vesicles in a Sex-Dependent Manner. Neurochem Res 2022; 47:2263-2277. [PMID: 35501523 PMCID: PMC9352616 DOI: 10.1007/s11064-022-03612-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/15/2022] [Accepted: 04/16/2022] [Indexed: 01/08/2023]
Abstract
In multiple neurodevelopmental and neurodegenerative disorders, endosomal changes correlate with changes in exosomes. We examined this linkage in the brain of mice that received cocaine injections for two weeks starting at 2.5 months of age. Cocaine caused a decrease in the number of both neuronal early and late endosomes and exosomes in the brains of male but not female mice. The response to cocaine in ovariectomized females mirrored male, demonstrating that these sex-differences in response to cocaine are driven by hormonal differences. Moreover, cocaine increased the amount of α-synuclein per exosome in the brain of females but did not affect exosomal α-synuclein content in the brain of males, a sex-difference eliminated by ovariectomy. Enhanced packaging of α-synuclein into female brain exosomes with the potential for propagation of pathology throughout the brain suggests a mechanism for the different response of females to chronic cocaine exposure as compared to males.
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Affiliation(s)
- Bryana R. Barreto
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Pasquale D’Acunzo
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016 USA
| | - Jonathan M. Ungania
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Sasmita Das
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Audrey Hashim
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Chris N. Goulbourne
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Stefanie Canals-Baker
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Mitsuo Saito
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Mariko Saito
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016 USA
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Henry Sershen
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016 USA
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
| | - Efrat Levy
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 USA
- Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016 USA
- Department of Biochemistry & Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016 USA
- NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016 USA
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Bahi DA, Dreyer JL. Chronic knockdown of the tetraspanin gene CD81 in the mouse nucleus accumbens modulates anxiety and ethanol-related behaviors. Physiol Behav 2022; 254:113894. [PMID: 35764142 DOI: 10.1016/j.physbeh.2022.113894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 10/17/2022]
Abstract
CD81, a member of the tetraspanin family, plays important roles in many physiological processes, such as cell motility, attachment, and entry. Yet, CD81 functions in the brain remain unclear. In this study, we investigated the effects of CD81 knockdown, using lentiviral vectors (LV), on anxiety- and ethanol-related behaviors. For this purpose, mice were stereotaxically injected with CD81 shRNA-expressing LV into the nucleus accumbens (Nacc) and were assessed for anxiety-like behavior using the elevated plus maze (EPM) and open field (OF) tests. Alcohol's sedative effects were studied using loss-of-righting-reflex (LORR) and voluntary ethanol intake was assessed using a two-bottle choice (TBC) procedure. Results showed that mice depleted of CD81 exhibited an anxiolytic-like response in the EPM and OF tests with no effect on locomotor activity. In addition, genetic reduction of CD81 in the Nacc increased mice' sensitivity to alcohol's sedative effects in the LORR test, although plasma alcohol concentrations were unaffected. Interestingly, CD81 loss-of-function-induced anxiolysis was accompanied by a significant decrease in ethanol, but not saccharin nor quinine, intake in the TBC procedure. Finally, and following CD81 mRNA quantification, Pearson's correlations showed a significant positive relationship between accumbal CD81 mRNA with anxiety and ethanol-related behaviors. Our data indicate that CD81 is implicated in the pathogenesis of anxiety and alcoholism. Indeed the targeted disruption of CD81, with the resultant decrease in CD81 mRNA in the Nacc, converted ethanol-"preferring" mice into ethanol "non-preferring" mice. Collectively, these findings demonstrate that future CD81-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.
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Affiliation(s)
- Dr Amine Bahi
- College of Medicine, Ajman University, Ajman, UAE; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE; Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, UAE.
| | - Jean-Luc Dreyer
- Division of Biochemistry, Department of Medicine, University of Fribourg, CH-1700, Fribourg, Switzerland
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Mass Spectrometry-Based Proteome Profiling of Extracellular Vesicles Derived from the Cerebrospinal Fluid of Adult Rhesus Monkeys Exposed to Cocaine throughout Gestation. Biomolecules 2022; 12:biom12040510. [PMID: 35454099 PMCID: PMC9026784 DOI: 10.3390/biom12040510] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 03/15/2022] [Accepted: 03/22/2022] [Indexed: 12/28/2022] Open
Abstract
Cocaine use disorder has been reported to cause transgenerational effects. However, due to the lack of standardized biomarkers, the effects of cocaine use during pregnancy on postnatal development and long-term neurobiological and behavioral outcomes have not been investigated thoroughly. Therefore, in this study, we examined extracellular vesicles (EVs) in adult (~12 years old) female and male rhesus monkeys prenatally exposed to cocaine (n = 11) and controls (n = 9). EVs were isolated from the cerebrospinal fluid (CSF) and characterized for the surface expression of specific tetraspanins, concentration (particles/mL), size distribution, and cargo proteins by mass spectrometry (MS). Transmission electron microscopy following immunogold labeling for tetraspanins (CD63, CD9, and CD81) confirmed the successful isolation of EVs. Nanoparticle tracking analyses showed that the majority of the particles were <200 nm in size, suggesting an enrichment for small EVs (sEV). Interestingly, the prenatally cocaine-exposed group showed ~54% less EV concentration in CSF compared to the control group. For each group, MS analyses identified a number of proteins loaded in CSF-EVs, many of which are commonly listed in the ExoCarta database. Ingenuity pathway analysis (IPA) demonstrated the association of cargo EV proteins with canonical pathways, diseases and disorders, upstream regulators, and top enriched network. Lastly, significantly altered proteins between groups were similarly characterized by IPA, suggesting that prenatal cocaine exposure could be potentially associated with long-term neuroinflammation and risk for neurodegenerative diseases. Overall, these results indicate that CSF-EVs could potentially serve as biomarkers to assess the transgenerational adverse effects due to prenatal cocaine exposure.
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Ipinmoroti AO, Crenshaw BJ, Pandit R, Kumar S, Sims B, Matthews QL. Human Adenovirus Serotype 3 Infection Modulates the Biogenesis and Composition of Lung Cell-Derived Extracellular Vesicles. J Immunol Res 2021; 2021:2958394. [PMID: 34926703 PMCID: PMC8677401 DOI: 10.1155/2021/2958394] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/16/2021] [Accepted: 11/01/2021] [Indexed: 11/21/2022] Open
Abstract
Adenovirus (Ad) is a major causal agent of acute respiratory infections. However, they are a powerful delivery system for gene therapy and vaccines. Some Ad serotypes antagonize the immune system leading to meningitis, conjunctivitis, gastroenteritis, and/or acute hemorrhagic cystitis. Studies have shown that the release of small, membrane-derived extracellular vesicles (EVs) may offer a mechanism by which viruses can enter cells via receptor-independent entry and how they influence disease pathogenesis and/or host protection considering their existence in almost all bodily fluids. We proposed that Ad3 could alter EV biogenesis, composition, and trafficking and may stimulate various immune responses in vitro. In the present study, we evaluated the impact of in vitro infection with Ad3 vector on EV biogenesis and composition in the human adenocarcinoma lung epithelial cell line A549. Cells were infected in an exosome-free media at different multiplicity of infections (MOIs) and time points. The cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and fluorometric calcein-AM. EVs were isolated via ultracentrifugation. Isolated EV proteins were quantified and evaluated via nanoparticle tracking, transmission electron microscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting assays. The cell viability significantly decreased with an increase in MOI and incubation time. A significant increase in particle mean sizes, concentrations, and total EV protein content was detected at higher MOIs when compared to uninfected cells (control group). A549 cell-derived EVs revealed the presence of TSG101, tetraspanins CD9 and CD63, and heat shock proteins 70 and 100 with significantly elevated levels of Rab5, 7, and 35 at higher MOIs (300, 750, and 1500) when compared to the controls. Our findings suggested Ad3 could modulate EV biogenesis, composition, and trafficking which could impact infection pathogenesis and disease progression. This study might suggest EVs could be diagnostic and therapeutic advancement to Ad infections and other related viral infections. However, further investigation is warranted to explore the underlying mechanism(s).
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Affiliation(s)
- Ayodeji O. Ipinmoroti
- Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA
| | - Brennetta J. Crenshaw
- Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA
| | - Rachana Pandit
- Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA
| | - Sanjay Kumar
- Departments of Pediatrics and Cell, Developmental and Integrative Biology, Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Brian Sims
- Departments of Pediatrics and Cell, Developmental and Integrative Biology, Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Qiana L. Matthews
- Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA
- Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA
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Margaroli C, Russell D. Extracellular Vesicles: Progress and Challenges in the Study of Human Immunodeficiency Virus and Cocaine-associated Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2021; 65:341-342. [PMID: 34166601 PMCID: PMC8525209 DOI: 10.1165/rcmb.2021-0222ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Camilla Margaroli
- Department of Medicine University of Alabama at Birmingham School of Medicine Birmingham, Alabama
| | - Derek Russell
- Department of Medicine University of Alabama at Birmingham Birmingham, Alabama
- Birmingham Veterans Affairs Medical Center Birmingham, Alabama
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Ibáñez F, Montesinos J, Area-Gomez E, Guerri C, Pascual M. Ethanol Induces Extracellular Vesicle Secretion by Altering Lipid Metabolism through the Mitochondria-Associated ER Membranes and Sphingomyelinases. Int J Mol Sci 2021; 22:ijms22168438. [PMID: 34445139 PMCID: PMC8395151 DOI: 10.3390/ijms22168438] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/27/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Recent evidence pinpoints extracellular vesicles (EVs) as key players in intercellular communication. Given the importance of cholesterol and sphingomyelin in EV biology, and the relevance of mitochondria-associated endoplasmic reticulum membranes (MAMs) in cholesterol/sphingomyelin homeostasis, we evaluated if MAMs and sphingomyelinases (SMases) could participate in ethanol-induced EV release. EVs were isolated from the extracellular medium of BV2 microglia treated or not with ethanol (50 and 100 mM). Radioactive metabolic tracers combined with thin layer chromatography were used as quantitative methods to assay phospholipid transfer, SMase activity and cholesterol uptake/esterification. Inhibitors of SMase (desipramine and GW4869) and MAM (cyclosporin A) activities were also utilized. Our data show that ethanol increases the secretion and inflammatory molecule concentration of EVs. Ethanol also upregulates MAM activity and alters lipid metabolism by increasing cholesterol uptake, cholesterol esterification and SMase activity in microglia. Notably, the inhibition of either SMase or MAM activity prevented the ethanol-induced increase in EV secretion. Collectively, these results strongly support a lipid-driven mechanism, specifically via SMases and MAM, to explain the effect of ethanol on EV secretion in glial cells.
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Affiliation(s)
- Francesc Ibáñez
- Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, 46012 Valencia, Spain; (F.I.); (C.G.)
| | - Jorge Montesinos
- Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA;
- Correspondence: (J.M.); (M.P.); Tel.: +34-961-625-635 (M.P.); Fax: +34-963-864-642 (M.P.)
| | - Estela Area-Gomez
- Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA;
| | - Consuelo Guerri
- Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, 46012 Valencia, Spain; (F.I.); (C.G.)
| | - María Pascual
- Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, 46012 Valencia, Spain; (F.I.); (C.G.)
- Department of Physiology, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- Correspondence: (J.M.); (M.P.); Tel.: +34-961-625-635 (M.P.); Fax: +34-963-864-642 (M.P.)
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11
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Landfield Q, Saito M, Hashim A, Canals-Baker S, Sershen H, Levy E, Saito M. Cocaine Induces Sex-Associated Changes in Lipid Profiles of Brain Extracellular Vesicles. Neurochem Res 2021; 46:2909-2922. [PMID: 34245421 PMCID: PMC8490334 DOI: 10.1007/s11064-021-03395-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/01/2021] [Accepted: 07/03/2021] [Indexed: 11/27/2022]
Abstract
Cocaine is a highly addictive stimulant with diverse effects on physiology. Recent studies indicate the involvement of extracellular vesicles (EVs) secreted by neural cells in the cocaine addiction process. It is hypothesized that cocaine affects secretion levels of EVs and their cargos, resulting in modulation of synaptic transmission and plasticity related to addiction physiology and pathology. Lipids present in EVs are important for EV formation and for intercellular lipid exchange that may trigger physiological and pathological responses, including neuroplasticity, neurotoxicity, and neuroinflammation. Specific lipids are highly enriched in EVs compared to parent cells, and recent studies suggest the involvement of various lipids in drug-induced synaptic plasticity during the development and maintenance of addiction processes. Therefore, we examined interstitial small EVs isolated from the brain of mice treated with either saline or cocaine, focusing on the effects of cocaine on the lipid composition of EVs. We demonstrate that 12 days of noncontingent repeated cocaine (10 mg/kg) injections to mice, which induce locomotor sensitization, cause lipid composition changes in brain EVs of male mice as compared with saline-injected controls. The most prominent change is the elevation of GD1a ganglioside in brain EVs of males. However, cocaine does not affect the EV lipid profiles of the brain in female mice. Understanding the relationship between lipid composition in EVs and vulnerability to cocaine addiction may provide insight into novel targets for therapies for addiction.
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Affiliation(s)
- Qwynn Landfield
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA
| | - Mitsuo Saito
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA
| | - Audrey Hashim
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA
| | - Stefanie Canals-Baker
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA
| | - Henry Sershen
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA
| | - Efrat Levy
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA
- Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
- NYU Neuroscience Institute, New York University School of Medicine, New York, NY, USA
- Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
| | - Mariko Saito
- Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA.
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
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