Proteomic Profiling of Exosomes Derived from Plasma of HIV-Infected Alcohol Drinkers and Cigarette Smokers

Mahon

et al. 2019

IJMS

Self Cite

The cytochrome P450 (CYP) family of enzymes is known to metabolize the majority of xenobiotics. Hepatocytes, powerhouses of CYP enzymes, are where most drugs are metabolized into non-toxic metabolites. Additional tissues/cells such as gut, kidneys, lungs, blood, and brain cells express selective CYP enzymes. Extrahepatic CYP enzymes, especially in kidneys, also metabolize drugs into excretable forms. However, extrahepatic cells express a much lower level of CYPs than hepatocytes. It is possible that the liver secretes CYP enzymes, which circulate via plasma and are eventually delivered to extrahepatic cells (e.g., brain cells). CYP circulation likely occurs via extracellular vesicles (EVs), which carry important biomolecules for delivery to distant cells. Recent studies have revealed an abundance of several CYPs in plasma EVs and other cell-derived EVs, and have demonstrated the role of CYP-containing EVs in xenobiotic-induced toxicity via cell–cell interactions. Thus, it is important to study the mechanism for packaging CYP into EVs, their circulation via plasma, and their role in extrahepatic cells. Future studies could help to find novel EV biomarkers and help to utilize EVs in novel interventions via CYP-containing EV drug delivery. This review mainly covers the abundance of CYPs in plasma EVs and EVs derived from CYP-expressing cells, as well as the potential role of EV CYPs in cell–cell communication and their application with respect to novel biomarkers and therapeutic interventions.

Section: Role Of Circulatory Cyps In Drug Metabolism and In Cell-cellmentioning

confidence: 57%

Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell–Cell Interactions

Gerth

Mahon

et al. 2019

IJMS

Self Cite

“…Our recent study with plasma EVs from HIV positive smokers has revealed some exciting information. First, we have shown the downregulation of properdin in the plasma EVs from HIV positive smokers, a protein in the human complementary system that interacts with viral proteins, suggesting a relatively high risk of secondary infections [49]. We also observed an alteration in the levels of CD9, CETP, and vitronectin (VTN) in plasma EVs from the HIV positive population; however, further studies are required to reach to any conclusion.…”

Section: Advances Since 2015mentioning

confidence: 85%

“…Conversely, HIV-infected macrophage-derived EVs lose this defense capacity, as evidenced by a higher viral load and increased cellular toxicity [39]. Proteomic and cytokine analyses of plasma EVs obtained from HIV-positive and negative smokers demonstrated a differential packaging of proteins in the EVs [37,49]. In addition, macrophage-derived EVs can readily cross the blood brain barrier, suggesting the potential role of EVs in either disseminating or alleviating HIV and HAND pathogenesis [30].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles in Smoking-Mediated HIV Pathogenesis and their Potential Role in Biomarker Discovery and Therapeutic Interventions

Haque

Gerth

et al. 2020

Cells

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In the last two decades, the mortality rate in people living with HIV/AIDS (PLWHA) has decreased significantly, resulting in an almost normal longevity in this population. However, a large portion of this population still endures a poor quality of life, mostly due to an increased inclination for substance abuse, including tobacco smoking. The prevalence of smoking in PLWHA is consistently higher than in HIV negative persons. A predisposition to cigarette smoking in the setting of HIV potentially leads to exacerbated HIV replication and a higher risk for developing neurocognitive and other CNS disorders. Oxidative stress and inflammation have been identified as mechanistic pathways in smoking-mediated HIV pathogenesis and HIV-associated neuropathogenesis. Extracellular vesicles (EVs), packaged with oxidative stress and inflammatory agents, show promise in understanding the underlying mechanisms of smoking-induced HIV pathogenesis via cell-cell interactions. This review focuses on recent advances in the field of EVs with an emphasis on smoking-mediated HIV pathogenesis and HIV-associated neuropathogenesis. This review also provides an overview of the potential applications of EVs in developing novel therapeutic carriers for the treatment of HIV-infected individuals who smoke, and in the discovery of novel biomarkers that are associated with HIV-smoking interactions in the CNS.

“…The EVs were further characterized by measuring their size using Zetasizer Nano-ZS (Malvern Instruments Inc, Malvern, UK) as described previously [24]. We also quantified and further validated the EVs by measuring acetylcholinesterase activity using the fluorescent Amplex ® Red Acetylcholine/Acetylcholinesterase Assay Kit (Molecular Probes, Invitrogen, Grand Island, NY, USA) as described previously [27]. Briefly, EVs isolated from 600 µL media was resuspended in 100 µL of 1X reaction buffer and incubated with a working solution of 400 µM Amplex Red reagent containing 2 U/mL horseradish peroxidase (HRP), 0.2 U/mL choline oxidase, and 100 µM acetylcholine.…”

Section: Evs Isolation and Characterizationmentioning

confidence: 99%

Extracellular Vesicles from Human Papilloma Virus-Infected Cervical Cancer Cells Enhance HIV-1 Replication in Differentiated U1 Cell Line

Ranjit

Sinha

et al. 2020

Viruses

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In the current study, we hypothesized that extracellular vesicles (EVs) secreted from human papilloma virus (HPV)-infected cervical cancer cells exacerbate human immunodeficiency virus (HIV)-1 replication in differentiated U1 cell line through an oxidative stress pathway. To test the hypothesis, we treated an HIV-1-infected macrophage cell line (U1) with HPV-infected Caski cell culture supernatant (CCS). We observed a significant increase in HIV-1 replication, which was associated with an increase in the expression of cytochrome P450 (CYPs 1A1 and 2A6) in the CCS-treated U1 cells. Furthermore, we isolated EVs from CCS (CCS-EVs), which showed the presence of CYPs (1A1, 2A6), superoxide dismutase 1 (SOD1), and HPV oncoproteins HPV16 E6. CCS-EVs when exposed to the U1 cells also significantly increased HIV-1 replication. Treatment of antioxidant, CYP1A1 and CYP2A6 inhibitors, and chemodietary agents with antioxidant properties significantly reduced the CCS and CCS-EVs mediated HIV-1 replication in U1 cells. Altogether, we demonstrate that cervical cancer cells exacerbate HIV-1 replication in differentiated U1 cell line via transferring CYPs and HPV oncoproteins through EVs. We also show that the viral replication occurs via CYP and oxidative stress pathways, and the viral replication is also reduced by chemodietary agents. This study provides important information regarding biological interactions between HPV and HIV-1 via EVs leading to enhanced HIV-1 replication.Viruses 2020, 12, 239 2 of 20 largely unknown. Therefore, there is a need to examine the biological interactions between HPV and HIV-1 to find better preventive and treatment strategies to reduce HIV-1 pathogenesis in HIV-1/HPV coinfected individuals.Evidences from previous reports show that cervical cancer cells constantly undergo oxidative stress [6][7][8]. Clinical samples from cervical cancer patients reveal a higher reactive oxygen species (ROS) level, higher oxidative damage, and a lower level of antioxidants, compared to samples from healthy individuals [9][10][11]. In vitro experiments also suggest a high level of ROS, profound downregulation in the genes associated with antioxidant proteins, such as superoxide dismutase 1 (SOD1), SOD2, SOD3, peroxiredoxin 1 (PRDX1), PRDX2, glutathione S-synthetase (GSS), and glutathione peroxidase 6 (GPX6), and high presence of Poly [ADP-ribose] polymerase 1 (PARP1), a marker of oxidative stress-induced DNA damage in cervical carcinoma-derived Caski cells [7]. HPV oncoproteins E6 and E7 stimulate the degradation of tumor-suppressor p53 protein [12], causing uncontrolled cell growth. The p53 protein, which primarily attributes to apoptosis and genomic stability, is also reported to have an antioxidant role [13]. Downregulation of p53 suppresses its antioxidant potential and renders the cells vulnerable to oxidative damage. Furthermore, the expression of HPV E6 and E7 oncoproteins alone is sufficient to cause oxidative stress. Marullo et al. demonstrated that HPV E6 and E7 proteins generate a chronic oxidative respo...