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Yuri Persidsky, MD, PhD

 

Yuri Persidsky, MD, PhD

 

Chairperson, Department of Pathology and Laboratory Medicine

Professor, Pathology and Laboratory Medicine

Telephone:  215-707-4353

Fax:  215-707-2781

Email: yuri.persidsky@tuhs.temple.edu

 

Department of Pathology and Laboratory Medicine

 

Educational Background:

 

Medical degree, Kiev State Medical Institute, Kiev, Ukraine

 

PhD, Pathology, Kiev Research Institute of Urology and Nephrology, Ukrainian Ministry of Health, Kiev, Ukraine

 

Residency, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE

 

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clinical Interests:

 
  • Surgical pathology
  • Nephropathology

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research Interests:

 

BBB protection in HIV infection: Barrier shielding effects of poly (ADP-ribose) polymerase (PARP) 1 inhibition

 

Prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the introduction of combined antiretroviral therapy. HAND is associated with elevation of pro-inflammatory factors in blood and subsets of activated infected monocytes, both shown to cause blood brain barrier (BBB) impairment that contributes to HAND. Therapeutic strategies that disrupt monocyte migration can slow progression of HIV infection and BBB injury, thereby ameliorating HAND. Previously, we focused on studies of molecular mechanisms of BBB injury and anti-inflammatory and barrier protective properties of glycogen synthase kinase (GSK)-3ß inhibition in neuroinflammation driven by HIV infection. We uncovered molecular mechanisms of BBB dysfunction [tight junction (TJ) phosphorylation, CD40/CD40 ligand interactions at BBB and signaling events behind the direct effects of HIV on brain endothelium]. We demonstrated barrier tightening following GSK-3ß suppression in brain endothelium due to TJ stabilization. We showed potent anti-inflammatory effects of GSK-3ß inhibition in brain endothelium in vitro and in vivo. GSKß inhibition in monocytes attenuated their adhesion/migration across the BBB, down regulated active integrin expression via suppression of the small GTPase, Rac1, and protected the BBB. Yet, BBB shielding properties or inhibition of monocyte migration/adhesion were not fully attained in vitro or in vivo, suggesting that additional pathways complimentary to GSK-3ß are necessary for the restitution of BBB function. In search of such molecules, we turned our attention to poly(ADP-ribose) polymerase-1 (PARP-1) and its inhibitors, recently recognized as anti-inflammatory/immune modulating agents with significant neuroprotective properties. Based upon preliminary data, we propose that PARP inhibition will attenuate BBB injury caused by HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Indeed, preliminary data indicate that PARP suppression in primary human brain microvascular endothelial cells (BMVEC) improved BBB integrity and augmented expression of TJ proteins. PARP inhibitors prevented barrier disruption caused by inflammatory factors, diminished monocyte adhesion/migration across a BBB model, down regulated adhesion molecules/pro-inflammatory molecules and decreased activity of RhoA/Rac1. In monocytes, PARP inhibitors down regulated the active beta-integrin that paralleled RhoA/Rac1 suppression. PARP inhibitors decreased expression of pro-inflammatory molecules and diminished HIV replication in human macrophages. Although the modulatory effects of PARP inhibitors on immune cells have been studied to some extent, nothing is known about their effects in the setting of HIV CNS infection. PARP inhibitors have now reached the stage of clinical testing for cancer treatment, assuring quick translation to therapy of immune/inflammatory disorders.

 

CNS injury caused by HIV-1 and alcohol: Protective effects of cannabinoid receptor (CB) 2 activation

 

Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. CB2 agonists possess potent anti-inflammatory and neuroprotective properties. We propose that CB2 activation will attenuate neuronal dysfunction and BBB injury caused by alcohol and HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Relevance of this idea is confirmed by our findings of augmented CB2 expression on brain endothelium in alcoholics, patients with HIV encephalitis and up-regulated CB2 expression in primary human brain microvascular endothelial cells (BMVEC) by alcohol and cytokines. CB2 agonists protected the barrier against inflammatory and alcohol insults, blocked monocyte migration across BBB and decreased expression of pro-inflammatory factors in activated BMVEC. CB2 agonist decreased leukocyte adhesion to brain endothelium and prevented enhanced BBB permeability in mice with systemic inflammation. We investigate the therapeutic potential of CB2 activation in diminution of neuroinflammation caused by the combined effects of alcohol and HIV-1.

 

Mechanisms and interventions for methamphetamine (METH) and HIV-1 induced CNS injury

 

METH an addictive stimulant has long lasting toxic effects on the central nervous system (CNS). Clinical studies indicated that METH dependence has an additive effect on neuropsychological deficits associated with HIV-1 infection. Oxidative stress, excitotoxicity, BBB impairment and glial cell activation, all have been independently implicated in the mechanisms of METH- and HIV-1-associated neurotoxicity. This project investigates mechanisms operative in HIV-1 CNS infection and METH abuse that lead to an overall increase in oxidative stress and NF-kB signaling resulting in impairment of astrocytes and endothelial cell function. We propose that METH-mediated oxidative stress in astrocytes leads to a down regulation exitotoxic amino acid transporter (EAAT) -2, the primary astrocyte glutamate scavenger, while in endothelial cells, such an increase in oxidative stress results in loss of BBB integrity. Preliminary data suggest that METH exposure caused ROS generation in astrocytes and human primary BMVEC, diminished EAAT-2 expression, in astrocytes, decreased BBB integrity in vitro that was restored by antioxidant treatment, caused decreased expression/re-distribution of tight junction proteins, enhanced adhesion and migration of monocytes across endothelial monolayers and activated small GTPases in BMVEC that were previously implicated in the BBB injury during HIV-1 encephalitis (HIVE). We showed increased permeability of BBB in vivo in animals exposed to METH prevented by antioxidant treatment. This project investigates a novel concept of mechanistic commonality, i.e. METH-mediated oxidative stress exerts its cell-specific effects in astrocytes and endothelial cells aggravating injury caused by HIV-1 CNS infection and delineate therapeutic options for these targets using in vivo studies.

 

Alcohol Abuse and HIV-1: Mechanisms of Combined CNS Injury and Interventions

 

Alcohol abuse and HIV-1 infection of CNS could result in combined toxic effects leading to neuronal demise and cognitive dysfunction. Our current grant application is focused on putative mechanisms of enhanced neurotoxicity in the setting of alcohol abuse and HIV-1 CNS infection. Specifically, we will study unique aspects of astrocyte dysfunction caused by HIV-1 CNS infection and alcohol abuse. We hypothesize that astrocyte dysfunction caused by alcohol metabolites and oxidative stress results in (1) increased glutamate levels via down regulation of excitatory amino acid transporter (EAAT-2, the primary astrocyte glutamate scavenger) causing neuronal injury; (2) production of pro-inflammatory factors (via activation of of Src kinases and phospholipase A2); and (3) enhanced activity of metalloproteases (MMPs) resulting in loss of BBB integrity. We mechanistically address the role of oxidative stress in astrocytes leading to production of pro-inflammatory molecules and impairment of glutamate uptake by astrocytes.

 

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board certification(s):

 

American Board of Pathology

 

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professional affiliations:

 

  • College of American Pathologists
  • American Society of Clinical Pathologists
  • American Society for Investigative Pathology
  • American Society of Virology
  • American Society of Neuroscience
  • International Society of Neuroimmunology
  • International Society of Neurovirology
  • Society for NeuroImmune Pharmacology
  • American Society of Neurochemistry

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

25119834. Hill J, Rom S, Ramirez SH, Persidsky Y, Emerging Roles of Pericytes in the Regulation of the Neurovascular Unit in Health and Disease. J Neuroimmune Pharmacol :()2014 Aug 14

24815068. Haskó J, Fazakas C, Molnár J, Nyúl-Tóth Á, Herman H, Hermenean A, Wilhelm I, Persidsky Y, Krizbai IA, CB2 receptor activation inhibits melanoma cell transmigration through the blood-brain barrier. Int J Mol Sci 15:5(8063-74)2014 May 8

24146950. Shuvaev VV, Han J, Tliba S, Arguiri E, Christofidou-Solomidou M, Ramirez SH, Dykstra H, Persidsky Y, Atochin DN, Huang PL, Muzykantov VR, Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo. PLoS One 8:10(e77002)2013

24055259. Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Pacher P, Persidsky Y, Selective activation of cannabinoid receptor 2 in leukocytes suppresses their engagement of the brain endothelium and protects the blood-brain barrier. Am J Pathol 183:5(1548-58)2013 Nov

23947613. Zhou Y, Bao R, Haigwood NL, Persidsky Y, Ho WZ, SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans. Retrovirology 10:(89)2013 Aug 15

23471521. Rom S, Persidsky Y, Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol 8:3(608-20)2013 Jun

23463725. Ramirez SH, Reichenbach NL, Fan S, Rom S, Merkel SF, Wang X, Ho WZ, Persidsky Y, Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. J Leukoc Biol 93:5(801-10)2013 May

23418486. Ramirez SH, Fan S, Dykstra H, Rom S, Mercer A, Reichenbach NL, Gofman L, Persidsky Y, Inhibition of glycogen synthase kinase 3ß promotes tight junction stability in brain endothelial cells by half-life extension of occludin and claudin-5. PLoS One 8:2(e55972)2013

23401273. Li J, Wang Y, Wang X, Ye L, Zhou Y, Persidsky Y, Ho W, Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages. Blood 121:15(2934-42)2013 Apr 11

23035017. Zhou Y, Guo M, Wang X, Li J, Wang Y, Ye L, Dai M, Zhou L, Persidsky Y, Ho W, TLR3 activation efficiency by high or low molecular mass poly I:C. Innate Immun 19:2(184-92)2013

22863953. Rom S, Fan S, Reichenbach N, Dykstra H, Ramirez SH, Persidsky Y, Glycogen synthase kinase 3ß inhibition prevents monocyte migration across brain endothelial cells via Rac1-GTPase suppression and down-regulation of active integrin conformation. Am J Pathol 181:4(1414-25)2012 Oct

22442067. Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y, Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32:12(4004-16)2012 Mar 21

22345580. Li H, Singh S, Potula R, Persidsky Y, Kanmogne GD, Dysregulation of claudin-5 in HIV-induced interstitial pneumonitis and lung vascular injury. Protective role of peroxisome proliferator-activated receptor-?. Am J Respir Crit Care Med 190:1(85-97)2014 Jul 1

21826700. Ashraf T, Ronaldson PT, Persidsky Y, Bendayan R, Regulation of P-glycoprotein by human immunodeficiency virus-1 in primary cultures of human fetal astrocytes. J Neurosci Res 89:11(1773-82)2011 Nov

21782933. Haorah J, Floreani NA, Knipe B, Persidsky Y, Stabilization of superoxide dismutase by acetyl-l-carnitine in human brain endothelium during alcohol exposure: novel protective approach. Free Radic Biol Med 51:8(1601-9)2011 Oct 15

21397004. Persidsky Y, Ho W, Ramirez SH, Potula R, Abood ME, Unterwald E, Tuma R, HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions. Brain Behav Immun 25 Suppl 1:(S61-70)2011 Jun

21324129. Li J, Ye L, Cook DR, Wang X, Liu J, Kolson DL, Persidsky Y, Ho WZ, Soybean-derived Bowman-Birk inhibitor inhibits neurotoxicity of LPS-activated macrophages. J Neuroinflammation 8:(15)2011 Feb 15

20708681. Rump TJ, Abdul Muneer PM, Szlachetka AM, Lamb A, Haorei C, Alikunju S, Xiong H, Keblesh J, Liu J, Zimmerman MC, Jones J, Donohue TM Jr, Persidsky Y, Haorah J, Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain. Free Radic Biol Med 49:10(1494-504)2010 Nov 30

20668216. Potula R, Hawkins BJ, Cenna JM, Fan S, Dykstra H, Ramirez SH, Morsey B, Brodie MR, Persidsky Y, Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol 185:5(2867-76)2010 Sep 1

20646875. Ye L, Wang S, Wang X, Zhou Y, Li J, Persidsky Y, Ho W, Alcohol impairs interferon signaling and enhances full cycle hepatitis C virus JFH-1 infection of human hepatocytes. Drug Alcohol Depend 112:1-2(107-16)2010 Nov 1

20631174. Ramirez SH, Fan S, Dykstra H, Reichenbach N, Del Valle L, Potula R, Phipps RP, Maggirwar SB, Persidsky Y, Dyad of CD40/CD40 ligand fosters neuroinflammation at the blood-brain barrier and is regulated via JNK signaling: implications for HIV-1 encephalitis. J Neurosci 30:28(9454-64)2010 Jul 14

20595955. Bernas MJ, Cardoso FL, Daley SK, Weinand ME, Campos AR, Ferreira AJ, Hoying JB, Witte MH, Brites D, Persidsky Y, Ramirez SH, Brito MA, Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood-brain barrier. Nat Protoc 5:7(1265-72)2010 Jul

20379791. Floreani NA, Rump TJ, Abdul Muneer PM, Alikunju S, Morsey BM, Brodie MR, Persidsky Y, Haorah J, Alcohol-induced interactive phosphorylation of Src and toll-like receptor regulates the secretion of inflammatory mediators by human astrocytes. J Neuroimmune Pharmacol 5:4(533-45)2010 Dec

20056834. Ramirez SH, Fan S, Zhang M, Papugani A, Reichenbach N, Dykstra H, Mercer AJ, Tuma RF, Persidsky Y, Inhibition of glycogen synthase kinase 3beta (GSK3beta) decreases inflammatory responses in brain endothelial cells. Am J Pathol 176:2(881-92)2010 Feb

19654589. Ramirez SH, Potula R, Fan S, Eidem T, Papugani A, Reichenbach N, Dykstra H, Weksler BB, Romero IA, Couraud PO, Persidsky Y, Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells. J Cereb Blood Flow Metab 29:12(1933-45)2009 Dec

19620291. Xiong W, MacTaggart J, Knispel R, Worth J, Persidsky Y, Baxter BT, Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol 183:4(2741-6)2009 Aug 15

19034671. Gendelman HE, Ding S, Gong N, Liu J, Ramirez SH, Persidsky Y, Mosley RL, Wang T, Volsky DJ, Xiong H, Monocyte chemotactic protein-1 regulates voltage-gated K+ channels and macrophage transmigration. J Neuroimmune Pharmacol 4:1(47-59)2009 Mar

18845238. Haorah J, Ramirez SH, Floreani N, Gorantla S, Morsey B, Persidsky Y, Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radic Biol Med 45:11(1542-50)2008 Dec 1

18670212. Potula R, Ramirez SH, Knipe B, Leibhart J, Schall K, Heilman D, Morsey B, Mercer A, Papugani A, Dou H, Persidsky Y, Peroxisome proliferator-activated receptor-gamma activation suppresses HIV-1 replication in an animal model of encephalitis. AIDS 22:13(1539-49)2008 Aug 20

18649402. Ronaldson PT, Persidsky Y, Bendayan R, Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 infection. Glia 56:16(1711-35)2008 Dec

18458093. Potula R, Persidsky Y, Adding fuel to the fire: methamphetamine enhances HIV infection. Am J Pathol 172:6(1467-70)2008 Jun

18209083. Ramirez SH, Heilman D, Morsey B, Potula R, Haorah J, Persidsky Y, Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses Rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. J Immunol 180:3(1854-65)2008 Feb 1

18187566. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T, Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol 172:2(521-33)2008 Feb

18040841. Persidsky Y, Fox H, Battle of animal models. J Neuroimmune Pharmacol 2:2(171-7)2007 Jun

18040811. Berman JW, Carson MJ, Chang L, Cox BM, Fox HS, Gonzalez RG, Hanson GR, Hauser KF, Ho WZ, Hong JS, Major EO, Maragos WF, Masliah E, McArthur JC, Miller DB, Nath A, O'Callaghan JP, Persidsky Y, Power C, Rogers TJ, Royal W 3rd, NeuroAIDS, drug abuse, and inflammation: building collaborative research activities. J Neuroimmune Pharmacol 1:4(351-99)2006 Dec

18040800. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD, Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1:3(223-36)2006 Sep

18003888. Chaudhuri A, Yang B, Gendelman HE, Persidsky Y, Kanmogne GD, STAT1 signaling modulates HIV-1-induced inflammatory responses and leukocyte transmigration across the blood-brain barrier. Blood 111:4(2062-72)2008 Feb 15

17948266. Liu J, Johnson TV, Lin J, Ramirez SH, Bronich TK, Caplan S, Persidsky Y, Gendelman HE, Kipnis J, T cell independent mechanism for copolymer-1-induced neuroprotection. Eur J Immunol 37:11(3143-54)2007 Nov

17943953. Haorah J, Schall K, Ramirez SH, Persidsky Y, Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuse. Glia 56:1(78-88)2008 Jan 1

17940540. Chaudhuri A, Duan F, Morsey B, Persidsky Y, Kanmogne GD, HIV-1 activates proinflammatory and interferon-inducible genes in human brain microvascular endothelial cells: putative mechanisms of blood-brain barrier dysfunction. J Cereb Blood Flow Metab 28:4(697-711)2008 Apr

17321604. Ricardo-Dukelow M, Kadiu I, Rozek W, Schlautman J, Persidsky Y, Ciborowski P, Kanmogne GD, Gendelman HE, HIV-1 infected monocyte-derived macrophages affect the human brain microvascular endothelial cell proteome: new insights into blood-brain barrier dysfunction for HIV-1-associated dementia. J Neuroimmunol 185:1-2(37-46)2007 Apr

17250680. Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y, Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J Neurochem 101:2(566-76)2007 Apr

17241155. Haorah J, Knipe B, Gorantla S, Zheng J, Persidsky Y, Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release. J Neurochem 100:2(324-36)2007 Jan

17173547. Hauser KF, El-Hage N, Stiene-Martin A, Maragos WF, Nath A, Persidsky Y, Volsky DJ, Knapp PE, HIV-1 neuropathogenesis: glial mechanisms revealed through substance abuse. J Neurochem 100:3(567-86)2007 Feb

17063148. Spitzenberger TJ, Heilman D, Diekmann C, Batrakova EV, Kabanov AV, Gendelman HE, Elmquist WF, Persidsky Y, Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis. J Cereb Blood Flow Metab 27:5(1033-42)2007 May

16972904. Persidsky Y, Poluektova L, Immune privilege and HIV-1 persistence in the CNS. Immunol Rev 213:(180-94)2006 Oct

16685256. Kanmogne GD, Schall K, Leibhart J, Knipe B, Gendelman HE, Persidsky Y, HIV-1 gp120 compromises blood-brain barrier integrity and enhances monocyte migration across blood-brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab 27:1(123-34)2007 Jan

16565506. Potula R, Haorah J, Knipe B, Leibhart J, Chrastil J, Heilman D, Dou H, Reddy R, Ghorpade A, Persidsky Y, Alcohol abuse enhances neuroinflammation and impairs immune responses in an animal model of human immunodeficiency virus-1 encephalitis. Am J Pathol 168:4(1335-44)2006 Apr

16478881. Persidsky Y, Heilman D, Haorah J, Zelivyanskaya M, Persidsky R, Weber GA, Shimokawa H, Kaibuchi K, Ikezu T, Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE). Blood 107:12(4770-80)2006 Jun 15

16260388. Persidsky Y, Potula R, Haorah J, Rodent model systems for studies of HIV-1 associated dementia. Neurotox Res 8:1-2(91-106)2005 Oct

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