Extracellular Vesicles: Intercellular Mediators in Alcohol-Induced Pathologies

  • Mohammad A. Rahman
  • Benjamin J. Patters
  • Sunitha Kodidela
  • Santosh KumarEmail author


Though alcoholic liver injury plays the primary role in direct alcohol-related morbidity, alcohol consumption is also interlinked with many other diseases in extra-hepatic tissues/organs. The mechanism of alcoholic tissue injury is well documented, however the mechanisms that affect extra-hepatic tissues have not yet been well defined. Extracellular vesicles (EVs) such as exosomes and microvesicles, have been identified as key components of alcohol-induced extra-hepatic effects. We have reviewed the recent findings on the potential impact of alcohol-modified EVs/exosomes production and their downstream effects on extra-hepatic tissues. In this review, we discuss the available information on the cross-talk between hepatocytes and immune cells via EV/exosomal cargos (miRNA, mRNA, protein, etc.) in alcoholic liver diseases. We also discuss the effects of alcohol exposure on the contents of EVs/exosomes derived from various extra-hepatic tissues and their associated pathological consequences on recipient cells. Finally, we speculate on other potential EV/exosomal agents that may mediate alcohol-induced tissue damage.

Graphical Abstract

Alcohol can alter contents of extracellular vesicles (EVs) (e.g. exosomes) such as miRNAs, protein, cytokines, etc. in hepatic and extra-hepatic cells. The transfer of these alcohol modified EVs to nearby or distant cells can play vital role in inflammatory pathways in alcohol induced pathogenesis/comorbidities.


Alcohol Extracellular vesicles Exosomes Toxicity Biomarker Inflammation 



The authors are supported by the National Institutes of Health under Grants (AA022063) and (DA047178).

Compliance with Ethical Standards

Conflicts of Interest

The authors declare no conflict of interest.


  1. Akers JC, Gonda D, Kim R, Carter BS, Chen CC (2013) Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neuro-Oncol 113(1):1–11CrossRefGoogle Scholar
  2. Amer SM, Bhopale KK, Kakumanu RD, Popov VL, Rampy BA, el-Mehallawi IH, Ashmawy MM, Shakeel Ansari GA, Kaphalia BS (2018) Hepatic alcohol dehydrogenase deficiency induces pancreatic injury in chronic ethanol feeding model of deer mice. Exp Mol Pathol 104(1):89–97CrossRefPubMedPubMedCentralGoogle Scholar
  3. Amritraj A, Wang Y, Revett TJ, Vergote D, Westaway D, Kar S (2013) Role of cathepsin D in U18666A-induced neuronal cell death: potential implication in Niemann-pick type C disease pathogenesis. J Biol Chem 288(5):3136–3152CrossRefPubMedGoogle Scholar
  4. An S, Zheng Y, Bleu T (2000) Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5. J Biol Chem 275(1):288–296CrossRefPubMedGoogle Scholar
  5. Ande A, Sinha N, Rao PSS, McArthur CP, Ayuk L, Achu PN, Njinda A, Kumar A, Kumar S (2015) Enhanced oxidative stress by alcohol use in HIV+ patients: possible involvement of cytochrome P450 2E1 and antioxidant enzymes. AIDS Res Ther 12:29CrossRefPubMedPubMedCentralGoogle Scholar
  6. Anderson M, Kashanchi F, Jacobson S (2018) Role of exosomes in human retroviral mediated disorders. J NeuroImmune Pharmacol 13(3):279–291CrossRefPubMedGoogle Scholar
  7. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18(11):1584–1593CrossRefPubMedPubMedCentralGoogle Scholar
  8. Atienzar-Aroca S, Flores-Bellver M, Serrano-Heras G, Martinez-Gil N, Barcia JM, Aparicio S, Perez-Cremades D, Garcia-Verdugo JM, Diaz-Llopis M, Romero FJ, Sancho-Pelluz J (2016) Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells. J Cell Mol Med 20(8):1457–1466CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J, Alao H, Kodys K, Szabo G (2012) Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56(5):1946–1957CrossRefPubMedPubMedCentralGoogle Scholar
  10. Basra G, Basra S, Parupudi S (2011) Symptoms and signs of acute alcoholic hepatitis. World J Hepatol 3(5):118–120CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bonner AB, Swann ME, Marway JS, Heap LC, Preedy VR (1995) Lysosomal and nonlysosomal protease activities of the brain in response to ethanol feeding. Alcohol 12(6):505–509CrossRefPubMedGoogle Scholar
  12. Bradford BU, Kono H, Isayama F, Kosyk O, Wheeler MD, Akiyama TE, Bleye L, Krausz KW, Gonzalez FJ, Koop DR, Rusyn I (2005) Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology 41(2):336–344CrossRefPubMedGoogle Scholar
  13. Brandon-Warner E, Feilen NA, Culberson CR, Field CO, deLemos AS, Russo MW, Schrum LW (2016a) Processing of miR17-92 cluster in hepatic stellate cells promotes hepatic Fibrogenesis during alcohol-induced injury. Alcohol Clin Exp Res 40(7):1430–1442CrossRefPubMedPubMedCentralGoogle Scholar
  14. Brandon-Warner E, Feilen NA, Culberson CR, Field CO, deLemos AS, Russo MW, Schrum LW (2016b) Processing of miR17-92 cluster in hepatic stellate cells promotes hepatic Fibrogenesis during alcohol-induced injury. Alcohol Clin Exp Res 40(7):1430–1442CrossRefPubMedPubMedCentralGoogle Scholar
  15. Breitkopf K, Haas S, Wiercinska E, Singer MV, Dooley S (2005) Anti-TGF-beta strategies for the treatment of chronic liver disease. Alcohol Clin Exp Res 29(11 Suppl):121s–131sCrossRefPubMedGoogle Scholar
  16. Brown GC, Vilalta A (2015) How microglia kill neurons. Brain Res 1628(Pt B):288–297CrossRefPubMedGoogle Scholar
  17. Byrd CA, Bornmann W, Erdjument-Bromage H, Tempst P, Pavletich N, Rosen N, Nathan CF, Ding A (1999) Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide. Proc Natl Acad Sci U S A 96(10):5645–5650CrossRefPubMedPubMedCentralGoogle Scholar
  18. Castino R et al (2007) Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells. Free Radic Biol Med 42(9):1305–1316CrossRefPubMedGoogle Scholar
  19. Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA (1995) Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14(3):671–680CrossRefPubMedGoogle Scholar
  20. Cederbaum AI (2012) Alcohol metabolism. Clin Liver Dis 16(4):667–685CrossRefPubMedPubMedCentralGoogle Scholar
  21. Celli R, Zhang X (2014) Pathology of alcoholic liver disease. J Clin Transl Hepatol 2(2):103–109PubMedPubMedCentralGoogle Scholar
  22. Chan C, Levitsky J (2016) Infection and alcoholic liver disease. Clin Liver Dis 20(3):595–606CrossRefPubMedGoogle Scholar
  23. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65(14):6029–6033CrossRefPubMedGoogle Scholar
  24. Chargaff E, West R (1946) The biological significance of the thromboplastic protein of blood. J Biol Chem 166(1):189–197PubMedPubMedCentralGoogle Scholar
  25. Charrier AL, Brigstock DR (2010) Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis. Lab Investig 90(8):1179–1188CrossRefPubMedGoogle Scholar
  26. Charrier A, Chen R, Chen L, Kemper S, Hattori T, Takigawa M, Brigstock DR (2014) Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes. J Cell Commun Signal 8(2):147–156CrossRefPubMedPubMedCentralGoogle Scholar
  27. Chen W, Tang Z, Fortina P, Patel P, Addya S, Surrey S, Acheampong EA, Mukhtar M, Pomerantz RJ (2005) Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways. Virology 334(1):59–73CrossRefPubMedGoogle Scholar
  28. Cho YE, Mezey E, Hardwick JP, Salem N Jr, Clemens DL, Song BJ (2017) Increased ethanol-inducible cytochrome P450-2E1 and cytochrome P450 isoforms in exosomes of alcohol-exposed rodents and patients with alcoholism through oxidative and endoplasmic reticulum stress. Hepatol Commun 1(7):675–690CrossRefPubMedPubMedCentralGoogle Scholar
  29. Cho YE, Seo W, Kim DK, Moon PG, Kim SH, Lee BH, Song BJ, Baek MC (2018a) Exogenous exosomes from mice with acetaminophen-induced liver injury promote toxicity in the recipient hepatocytes and mice. Sci Rep 8(1):16070CrossRefPubMedPubMedCentralGoogle Scholar
  30. Cho YE, Song BJ, Akbar M, Baek MC (2018b) Extracellular vesicles as potential biomarkers for alcohol- and drug-induced liver injury and their therapeutic applications. Pharmacol Ther 187:180–194CrossRefPubMedGoogle Scholar
  31. Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J (2006) Cytokines and alcohol. Alcohol Clin Exp Res 30(4):720–730CrossRefPubMedGoogle Scholar
  32. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant Protein-1 (MCP-1): An overview. J Interf Cytokine Res 29(6):313–326CrossRefGoogle Scholar
  33. Di Domenico F, Tramutola A, Perluigi M (2016) Cathepsin D as a therapeutic target in Alzheimer's disease. Expert Opin Ther Targets 20(12):1393–1395CrossRefPubMedGoogle Scholar
  34. Dippold RP, Vadigepalli R, Gonye GE, Hoek JB (2012) Chronic ethanol feeding enhances miR-21 induction during liver regeneration while inhibiting proliferation in rats. Am J Physiol Gastrointest Liver Physiol 303(6):G733–G743CrossRefPubMedPubMedCentralGoogle Scholar
  35. Dong Q, Kelkar S, Xiao Y, Joshi-Barve S, McClain CJ, Barve SS (2000) Ethanol enhances TNF-alpha-inducible NFkappaB activation and HIV-1-LTR transcription in CD4+ Jurkat T lymphocytes. J Lab Clin Med 136(5):333–343CrossRefPubMedGoogle Scholar
  36. Donohue TM, Curry-McCoy TV, Nanji AA, Kharbanda KK, Osna NA, Radio SJ, Todero SL, White RL, Casey CA (2007) Lysosomal leakage and lack of adaptation of hepatoprotective enzyme contribute to enhanced susceptibility to ethanol-induced liver injury in female rats. Alcohol Clin Exp Res 31(11):1944–1952CrossRefPubMedGoogle Scholar
  37. Downs CA, Dang VD, Johnson NM, Denslow ND, Alli AA (2018) Hydrogen peroxide stimulates Exosomal Cathepsin B regulation of the receptor for advanced glycation end-products (RAGE). J Cell Biochem 119(1):599–606CrossRefPubMedGoogle Scholar
  38. Embury CM, Dyavarshetty B, Lu Y, Wiederin JL, Ciborowski P, Gendelman HE, Kiyota T (2017) Cathepsin B improves ss-amyloidosis and learning and memory in models of Alzheimer's disease. J NeuroImmune Pharmacol 12(2):340–352CrossRefPubMedGoogle Scholar
  39. Fama R, Rosenbloom MJ, Nichols BN, Pfefferbaum A, Sullivan EV (2009) Working and episodic memory in HIV infection, alcoholism, and their comorbidity: baseline and 1-year follow-up examinations. Alcohol Clin Exp Res 33(10):1815–1824CrossRefPubMedPubMedCentralGoogle Scholar
  40. Fan Y, He JJ (2016) HIV-1 tat promotes lysosomal exocytosis in astrocytes and contributes to astrocyte-mediated tat neurotoxicity. J Biol Chem 291(43):22830–22840CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ge XT et al (2014) miR-21 improves the neurological outcome after traumatic brain injury in rats. Sci Rep 4:6718CrossRefPubMedPubMedCentralGoogle Scholar
  42. Gendron TF, McCartney S, Causevic E, Ko LW, Yen SH (2008) Ethanol enhances tau accumulation in neuroblastoma cells that inducibly express tau. Neurosci Lett 443(2):67–71CrossRefPubMedPubMedCentralGoogle Scholar
  43. Gendron K, Ferbeyre G, Heveker N, Brakier-Gingras L (2011) The activity of the HIV-1 IRES is stimulated by oxidative stress and controlled by a negative regulatory element. Nucleic Acids Res 39(3):902–912CrossRefPubMedGoogle Scholar
  44. Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D (2015) Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 85(1):40–47CrossRefPubMedPubMedCentralGoogle Scholar
  45. Gold B, Cankovic M, Furtado LV, Meier F, Gocke CD (2015) Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? A report of the association for molecular pathology. J Mol Diagn 17(3):209–224CrossRefPubMedPubMedCentralGoogle Scholar
  46. Hamlett ED, Goetzl EJ, Ledreux A, Vasilevko V, Boger HA, LaRosa A, Clark D, Carroll SL, Carmona-Iragui M, Fortea J, Mufson EJ, Sabbagh M, Mohammed AH, Hartley D, Doran E, Lott IT, Granholm AC (2017) Neuronal exosomes reveal Alzheimer's disease biomarkers in down syndrome. Alzheimers Dement 13(5):541–549CrossRefPubMedGoogle Scholar
  47. Hayes CN, Chayama K (2016) MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. Int J Mol Sci 17(3):280CrossRefPubMedPubMedCentralGoogle Scholar
  48. Higaki J, Catalano R, Guzzetta AW, Quon D, Navé JF, Tarnus C, D'Orchymont H, Cordell B (1996) Processing of beta-amyloid precursor protein by cathepsin D. J Biol Chem 271(50):31885–31893CrossRefPubMedGoogle Scholar
  49. Hook V, Hook G, Kindy M (2010) Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer's disease. Biol Chem 391(8):861–872CrossRefPubMedPubMedCentralGoogle Scholar
  50. Hook G, Yu J, Toneff T, Kindy M, Hook V (2014) Brain pyroglutamate amyloid-beta is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J Alzheimers Dis 41(1):129–149CrossRefPubMedPubMedCentralGoogle Scholar
  51. Huang WJ, Zhang X, Chen WW (2016) Association between alcohol and Alzheimer's disease. Exp Ther Med 12(3):1247–1250CrossRefPubMedPubMedCentralGoogle Scholar
  52. Ivanov AV et al (2016) Oxidative stress during HIV infection: mechanisms and consequences. Oxidative Med Cell Longev 2016:8910396CrossRefGoogle Scholar
  53. Janiszewski M, do Carmo AO, Pedro MA, Silva E, Knobel E, Laurindo FRM (2004) Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: a novel vascular redox pathway. Crit Care Med 32(3):818–825CrossRefPubMedGoogle Scholar
  54. Johnstone RM (2005) Revisiting the road to the discovery of exosomes. Blood Cells Mol Dis 34(3):214–219CrossRefPubMedGoogle Scholar
  55. Johnstone RM et al (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262(19):9412–9420PubMedGoogle Scholar
  56. Juskeviciute E, Dippold RP, Antony AN, Swarup A, Vadigepalli R, Hoek JB (2016) Inhibition of miR-21 rescues liver regeneration after partial hepatectomy in ethanol-fed rats. Am J Physiol Gastrointest Liver Physiol 311(5):G794–g806CrossRefPubMedPubMedCentralGoogle Scholar
  57. Kang GY, Bang JY, Choi AJ, Yoon J, Lee WC, Choi S, Yoon S, Kim HC, Baek JH, Park HS, Lim HJ, Chung H (2014) Exosomal proteins in the aqueous humor as novel biomarkers in patients with neovascular age-related macular degeneration. J Proteome Res 13(2):581–595CrossRefPubMedGoogle Scholar
  58. Kanninen KM, Bister N, Koistinaho J, Malm T (2016) Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta (BBA) - Mol Basis Dis 1862(3):403–410CrossRefGoogle Scholar
  59. Karpman D, Ståhl A-l, Arvidsson I (2017) Extracellular vesicles in renal disease. Nat Rev Nephrol 13:545–562CrossRefPubMedGoogle Scholar
  60. Kingham PJ, Pocock JM (2001) Microglial secreted cathepsin B induces neuronal apoptosis. J Neurochem 76(5):1475–1484CrossRefPubMedGoogle Scholar
  61. Kodidela S, Ranjit S, Sinha N, McArthur C, Kumar A, Kumar S (2018) Cytokine profiling of exosomes derived from the plasma of HIV-infected alcohol drinkers and cigarette smokers. PLoS One 13(7):e0201144CrossRefPubMedPubMedCentralGoogle Scholar
  62. Kowal J, Tkach M, Théry C (2014) Biogenesis and secretion of exosomes. Curr Opin Cell Biol 29:116–125CrossRefPubMedGoogle Scholar
  63. Kumar S, Jin M, Ande A, Sinha N, Silverstein PS, Kumar A (2012) Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes. Expert Opin Drug Metab Toxicol 8(11):1363–1375CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kumar S, Sinha N, Gerth KA, Rahman MA, Yallapu MM, Midde NM (2017) Specific packaging and circulation of cytochromes P450, especially 2E1 isozyme, in human plasma exosomes and their implications in cellular communications. Biochem Biophys Res Commun 491(3):675–680CrossRefPubMedPubMedCentralGoogle Scholar
  65. Lamichhane TN, Leung CA, Douti LY, Jay SM (2017) Ethanol induces enhanced vascularization bioactivity of endothelial cell-derived extracellular vesicles via regulation of MicroRNAs and long non-coding RNAs. Sci Rep 7(1):13794CrossRefPubMedPubMedCentralGoogle Scholar
  66. Lazarevic AM et al (2000) Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to the duration of heavy drinking. J Am Coll Cardiol 35(6):1599–1606CrossRefPubMedGoogle Scholar
  67. Li S, Li Y, Chen B, Zhao J, Yu S, Tang Y, Zheng Q, Li Y, Wang P, He X, Huang S (2018) exoRBase: a database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res 46(D1):D106–D112CrossRefPubMedGoogle Scholar
  68. M HR et al (2017) Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci 18(3)Google Scholar
  69. Madison MN, Okeoma CM (2015) Exosomes: implications in HIV-1 pathogenesis. Viruses 7(7):4093–4118CrossRefPubMedPubMedCentralGoogle Scholar
  70. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA (2013) Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 304(7):H954–H965CrossRefPubMedPubMedCentralGoogle Scholar
  71. Meyerhoff DJ (2001) Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health 25(4):288–298PubMedGoogle Scholar
  72. Midde NM, Rahman MA, Rathi C, Li J, Meibohm B, Li W, Kumar S (2016) Effect of ethanol on the metabolic characteristics of HIV-1 integrase inhibitor Elvitegravir and Elvitegravir/Cobicistat with CYP3A: An analysis using a newly developed LC-MS/MS method. PLoS One 11(2):e0149225CrossRefPubMedPubMedCentralGoogle Scholar
  73. Midde NM, Sinha N, Lukka PB, Meibohm B, Kumar S (2017) Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells. PLoS One 12(2):e0172628CrossRefPubMedPubMedCentralGoogle Scholar
  74. Miranda RC, Pietrzykowski AZ, Tang Y, Sathyan P, Mayfield D, Keshavarzian A, Sampson W, Hereld D (2010) MicroRNAs: master regulators of ethanol abuse and toxicity? Alcohol Clin Exp Res 34(4):575–587CrossRefPubMedPubMedCentralGoogle Scholar
  75. Momen-Heravi F, Bala S (2018) Extracellular vesicles in oral squamous carcinoma carry oncogenic miRNA profile and reprogram monocytes via NF-kappaB pathway. Oncotarget 9(78):34838–34854CrossRefPubMedPubMedCentralGoogle Scholar
  76. Momen-Heravi F, Saha B, Kodys K, Catalano D, Satishchandran A, Szabo G (2015) Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med 13:261CrossRefPubMedPubMedCentralGoogle Scholar
  77. Morena F, Argentati C, Trotta R, Crispoltoni L, Stabile A, Pistilli A, di Baldassarre A, Calafiore R, Montanucci P, Basta G, Pedrinolla A, Smania N, Venturelli M, Schena F, Naro F, Emiliani C, Rende M, Martino S (2017) A comparison of lysosomal enzymes expression levels in peripheral blood of mild- and severe-Alzheimer's disease and MCI patients: implications for regenerative medicine approaches. Int J Mol Sci 18(8)Google Scholar
  78. Nojima H, Konishi T, Freeman CM, Schuster RM, Japtok L, Kleuser B, Edwards MJ, Gulbins E, Lentsch AB (2016) Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes. PLoS One 11(8):e0161443CrossRefPubMedPubMedCentralGoogle Scholar
  79. Patters BJ, Kumar S (2018) The role of exosomal transport of viral agents in persisetnt HIV pathogenesis.Retrovirology 15(1):79–81Google Scholar
  80. Qin L, Crews FT (2012) NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. J Neuroinflammation 9:5PubMedPubMedCentralGoogle Scholar
  81. Qin Y, Peng Y, Zhao W, Pan J, Ksiezak-Reding H, Cardozo C, Wu Y, Divieti Pajevic P, Bonewald LF, Bauman WA, Qin W (2017) Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: a novel mechanism in muscle-bone communication. J Biol Chem 292(26):11021–11033CrossRefPubMedPubMedCentralGoogle Scholar
  82. Rahman MA, Gong Y, Kumar S (2018) In vitro evaluation of structural analogs of diallyl sulfide as novel CYP2E1 inhibitors for their protective effect against xenobiotic-induced toxicity and HIV replication. Toxicol Lett 292:31–38CrossRefPubMedGoogle Scholar
  83. Revenfeld AL et al (2014) Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. Clin Ther 36(6):830–846CrossRefPubMedGoogle Scholar
  84. Ribeiro MF et al (2013) Exosomes function in pro- and anti-angiogenesis. Curr Angiogenesis 2(1):54–59Google Scholar
  85. Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14(3):195–208CrossRefPubMedPubMedCentralGoogle Scholar
  86. Rusyn I, Bataller R (2013) Alcohol and toxicity. J Hepatol 59(2):387–388CrossRefPubMedPubMedCentralGoogle Scholar
  87. Saha B, Momen-Heravi F, Kodys K, Szabo G (2016) MicroRNA cargo of extracellular vesicles from alcohol-exposed monocytes signals naive monocytes to differentiate into M2 macrophages. J Biol Chem 291(1):149–159CrossRefPubMedGoogle Scholar
  88. Saha B, Momen-Heravi F, Furi I, Kodys K, Catalano D, Gangopadhyay A, Haraszti R, Satishchandran A, Iracheta-Vellve A, Adejumo A, Shaffer SA, Szabo G (2018) Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90. Hepatology 67(5):1986–2000CrossRefPubMedGoogle Scholar
  89. Saito M, Chakraborty G, Mao RF, Paik SM, Vadasz C, Saito M (2010) Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. Neurochem Res 35(4):651–659CrossRefPubMedPubMedCentralGoogle Scholar
  90. Saman S, Kim WH, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NCY, Hall GF (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287(6):3842–3849CrossRefPubMedGoogle Scholar
  91. Sampey GC et al (2014) Exosomes and their role in CNS viral infections. J Neuro-Oncol 20(3):199–208Google Scholar
  92. Santangelo A, Imbrucè P, Gardenghi B, Belli L, Agushi R, Tamanini A, Munari S, Bossi AM, Scambi I, Benati D, Mariotti R, di Gennaro G, Sbarbati A, Eccher A, Ricciardi GK, Ciceri EM, Sala F, Pinna G, Lippi G, Cabrini G, Dechecchi MC (2018) A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neuro-Oncol 136(1):51–62CrossRefGoogle Scholar
  93. Segal AW (2008) The function of the NADPH oxidase of phagocytes and its relationship to other NOXs in plants, invertebrates, and mammals. Int J Biochem Cell Biol 40(4):604–618CrossRefPubMedPubMedCentralGoogle Scholar
  94. Seitz HK, Becker P (2007) Alcohol metabolism and cancer risk. Alcohol Res Health 30(1):38–41 44-7PubMedPubMedCentralGoogle Scholar
  95. Self RL, Mulholland PJ, Harris BR, Nath A, Prendergast MA (2004) Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein tat in the hippocampus are enhanced by prior ethanol treatment. Alcohol Clin Exp Res 28(12):1916–1924CrossRefPubMedGoogle Scholar
  96. Setshedi M, Wands JR, de la Monte SM (2010) Acetaldehyde adducts in alcoholic liver disease. Oxidative Med Cell Longev 3(3):178–185CrossRefGoogle Scholar
  97. Shi R et al (2015) Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget 6(29):26971–26981CrossRefPubMedPubMedCentralGoogle Scholar
  98. Silverstein PS, Kumar A (2014) HIV-1 and alcohol: interactions in the central nervous system. Alcohol Clin Exp Res 38(3):604–610CrossRefPubMedGoogle Scholar
  99. Simic G et al (2016) Tau protein hyperphosphorylation and aggregation in Alzheimer's disease and other Tauopathies, and possible neuroprotective strategies. Biomolecules 6(1):6CrossRefPubMedPubMedCentralGoogle Scholar
  100. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH (2018) ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol 113(2):175–194CrossRefPubMedGoogle Scholar
  101. Snir JA, Suchy M, Bindseil GA, Kovacs M, Chronik BA, Hudson RHE, Pasternak SH, Bartha R (2018) An aspartyl Cathepsin targeted PET agent: application in an Alzheimer's disease mouse model. J Alzheimers Dis 61(3):1241–1252CrossRefPubMedGoogle Scholar
  102. Suchorska WM, Lach MS (2016) The role of exosomes in tumor progression and metastasis (review). Oncol Rep 35(3):1237–1244CrossRefPubMedGoogle Scholar
  103. Todorova D, Simoncini S, Lacroix R, Sabatier F, Dignat-George F (2017) Extracellular vesicles in angiogenesis. Circ Res 120(10):1658–1673CrossRefPubMedPubMedCentralGoogle Scholar
  104. Verma VK, Li H, Wang R, Hirsova P, Mushref M, Liu Y, Cao S, Contreras PC, Malhi H, Kamath PS, Gores GJ, Shah VH (2016) Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol 64(3):651–660CrossRefPubMedGoogle Scholar
  105. Viñas JL, Spence M, Gutsol A, Knoll W, Burger D, Zimpelmann J, Allan DS, Burns KD (2018) Receptor-ligand interaction mediates targeting of endothelial Colony forming cell-derived exosomes to the kidney after ischemic injury. Sci Rep 8(1):16320–16320CrossRefPubMedPubMedCentralGoogle Scholar
  106. Visani M, de Biase D, Marucci G, Cerasoli S, Nigrisoli E, Bacchi Reggiani ML, Albani F, Baruzzi A, Pession A, the PERNO study group (2014) Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III. Mol Oncol 8(2):417–430CrossRefPubMedGoogle Scholar
  107. Wang HJ, Gao B, Zakhari S, Nagy LE (2012a) Inflammation in alcoholic liver disease. Annu Rev Nutr 32:343–368CrossRefPubMedPubMedCentralGoogle Scholar
  108. Wang X, Ke Z, Chen G, Xu M, Bower KA, Frank JA, Zhang Z, Shi X, Luo J (2012b) Cdc42-dependent activation of NADPH oxidase is involved in ethanol-induced neuronal oxidative stress. PLoS One 7(5):e38075CrossRefPubMedPubMedCentralGoogle Scholar
  109. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta 1842(8):1240–1247CrossRefPubMedGoogle Scholar
  110. World Health organization (2014) Global status report on alcohol health. WHO library cataloguing-in-publication data: 1–85Google Scholar
  111. Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13(3):269–288CrossRefPubMedGoogle Scholar
  112. Wu Z, Ni J, Liu Y, Teeling JL, Takayama F, Collcutt A, Ibbett P, Nakanishi H (2017) Cathepsin B plays a critical role in inducing Alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun 65:350–361CrossRefPubMedGoogle Scholar
  113. Xiao D, Ohlendorf J, Chen Y, Taylor DD, Rai SN, Waigel S, Zacharias W, Hao H, McMasters KM (2012) Identifying mRNA, MicroRNA and protein profiles of melanoma exosomes. PLoS One 7(10):e46874CrossRefPubMedPubMedCentralGoogle Scholar
  114. Yáñez-Mó M, Siljander PRM, Andreu Z, Bedina Zavec A, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NHH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, Manček-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-‘t Hoen ENM, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pállinger É, del Portillo HA, Reventós J, Rigau M, Rohde E, Sammar M, Sánchez-Madrid F, Santarém N, Schallmoser K, Stampe Ostenfeld M, Stoorvogel W, Stukelj R, van der Grein SG, Helena Vasconcelos M, Wauben MHM, de Wever O (2015) Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 4:27066–27066CrossRefPubMedGoogle Scholar
  115. Yelamanchili SV, Lamberty BG, Rennard DA, Morsey BM, Hochfelder CG, Meays BM, Levy E, Fox HS (2015) MiR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in SIV neurological disease. PLoS Pathog 11(7):e1005032CrossRefPubMedPubMedCentralGoogle Scholar
  116. Zenon F et al (2015) HIV-infected microglia mediate cathepsin B-induced neurotoxicity. J Neuro-Oncol 21(5):544–558Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of Tennessee Health Science CenterMemphisUSA

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