Keiichi Enjyoji

Keiichi Enjyoji
Continuum Health Partners | CHP · Beth Israel Medical Center

Doctor of Philosophy

About

56
Publications
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3,363
Citations

Publications

Publications (56)
Article
Full-text available
Immunosuppressive cells accumulating in the tumor microenvironment constitute a formidable barrier that interferes with current immunotherapeutic approaches. A unifying feature of these tumor-associated immune and vascular endothelial cells appears to be the elevated expression of ectonucleotidase CD39, which in tandem with ecto-5′-nucleotidase CD7...
Article
Background Ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), also known as CD39L3, is the dominant ectonucleotidase expressed by beta cells in the islet of Langerhans and on nerves. NTPDase3 catalyzes the conversion of extracellular ATP and ADP to AMP and modulates purinergic signaling. Previous studies have shown that NTPDase3 decrease...
Article
Full-text available
Purinergic signaling is important in the activation and differentiation of macrophages, which play divergent roles in the pathophysiology of liver fibrosis. The ectonucleotidase CD39 is known to modulate the immunoregulatory phenotype of macrophages, but whether this specifically impacts cholestatic liver injury is unknown. Here, we investigated th...
Article
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CD39 scavenges extracellular ATP and ADP, ultimately generating adenosine, a nucleoside, which has anti-inflammatory effects in the vasculature. We have evaluated the role of CD39 in the development of atherosclerosis in hyperlipidemic mice. ApoE KO (Cd39+/+/ApoE-/-) and Cd39/ApoE double knockout (Cd39-/-/ApoE-/-, DKO) mice were maintained on chow...
Article
Nerve cells are continuously generated from stem cells in the adult mammalian subventricular zone (SVZ) and hippocampal dentate gyrus. We have previously noted that stem/progenitor cells in the SVZ and the subgranular layer (SGL) of the dentate gyrus express high levels of plasma membrane-bound nucleoside triphosphate diphosphohydrolase 2 (NTPDase2...
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Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Excessive inflammation is a major cause of organ failure and mortality in sepsis. Ectonucleoside triphosphate diphosphohydrolase 1, ENTPDase1 (CD39) is a cell surface nucleotide-metabolizing enzyme, which degrades the extracellular purines ATP and ADP, thereby r...
Article
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Phosphohydrolysis of extracellular ATP and ADP is an essential step in purinergic signaling that regulates key pathophysiological processes, such as those linked to inflammation. Classically, this reaction has been known to occur in the pericellular milieu catalyzed by membrane bound cellular ecto-nucleotidases, which can be released in the form of...
Article
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Taste buds are unusual in requiring ATP as a transmitter to activate sensory nerve fibers. In response to taste stimuli, taste cells release ATP, activating purinergic receptors containing the P2X2 and P2X3 subunits on taste nerves. In turn, the released ATP is hydrolyzed to ADP by a plasma membrane nucleoside triphosphate previously identified as...
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Background Extracellular adenosine triphosphate (ATP) functions as a novel danger signal that boosts antitumor immunity and can also directly kill tumor cells. We have previously reported that chronic exposure of tumor cells to ATP provokes P2X7-mediated tumor cell death, by as yet incompletely defined molecular mechanisms. Methodology/Principal F...
Data
Extracellular ATP is cytotoxic for B16/F10 melanoma cells. A–C) Dose- and time-dependent responses of B16/F10 cells to ATP killing: cell viability/proliferation CCK-8 (A); real-time cell growth by xCELLigence (B); and representative live cell images by Celligo (C). D) Dose-dependent induction of autophagy by ATP in B16/F10 cells, as determined by W...
Data
Time- and dose-dependent responses of AKT, AMPK and mTOR to ATP-mediated signaling responses in tumor cells. A) Western blots for AKT, AMPK and mTOR pathway components post ATP treatment at various times and doses in B16/F10 cells (A). B) AMPK inhibitor compound C (CC) fully rescued ATP-induced mTOR inhibition in MCA38 cells in a dose-dependent man...
Data
Assessment of carbenoxolone, N-acetyl-cysteine, Z-VAD-fmk, and necrostatin-1 on ATP-P2X7 induced signaling or tumor cell death. A) Effects of carbenoxolone (CBX) and N-acetyl-cysteine (NAC) on ATP-initiated AKT, AMPK and mTOR signaling in MCA38 and B16/F10 cells, as examined by Western blot analysis. B) Effects of Z-VAD-fmk and necrostatin-1 on ATP...
Data
Impact of calcium signaling on AKT, AMPK and mTOR signaling transduction and tumor cell growth. A) Effects of BAPTA-AM on AKT, AMPK and mTOR signaling in B16/F10 cells, as analyzed by Western blotting. B) Effects of BAPTA-AM on MCA38 cell growth, as examined by CCK-8 and expressed as percentage of untreated controls. C–D) Impacts of thapsigargin (T...
Data
P2 receptor agonist and antagonist studies. A) B16/F10 cell viability at 24 hr post BzATP treatment, as determined by CCK-8. Data are normalized to untreated controls. B) Effects of suramin (100 µM,) on AKT, AMPK and mTOR pathways in MCA38 cells, as examined by Western blot analysis. C–D) P2X7 antagonist KN62 counteracted ATP-evoked signaling trans...
Data
P2X7 deficient B16/F10 cells. A) Knockdown of P2X7 in B16/F10 cells was validated by Western blotting. B–F) Differential effects of ATP on control and P2X7 KD B16/F10 cells: AKT- and AMPK-mTOR signaling by Western blotting (B); cell viability by CCK-8 (C); representative live cell images by Celligo (D); and real-time monitoring of cell growth by xC...
Article
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Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem...
Article
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Despite improvements in prevention and management of colorectal cancer (CRC), uncontrolled tumor growth with metastatic spread to distant organs remains an important clinical concern. Genetic deletion of CD39, the dominant vascular and immune cell ectonucleotidase, has been shown to delay tumor growth and blunt angiogenesis in mouse models of melan...
Article
Background Dysregulation of immune responses in inflammatory bowel diseases (IBD) results in intestinal inflammation and vascular injury while exacerbating systemic disease. CD39 is an ectonucleotidase, expressed by T regulatory cells and dendritic cells, that hydrolyzes extracellular nucleotides to modify those cellular immune responses implicated...
Article
Adenosine mediates immune suppression and is generated by the ectonucleotidases CD39 (ENTPD1) and CD73 that are expressed on vascular endothelial cells and regulatory T cells (Tregs). Although tumor-infiltrating immune cells include Foxp3(+) Tregs, it is not clear whether local adenosine generation by Tregs promotes tumor growth in a CD39-dependent...
Article
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How proliferative and inhibitory signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified transducer of ErbB2.1 (Tob1), a member of the PC3/BTG1 family of mito-inhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hep...
Article
Unlabelled: Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after pa...
Article
P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritone...
Article
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CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human g...
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The vascular ectonucleotidase ENTPD1 protects against renal injury and modulates glucose homeostasis in mouse models. We sought to determine whether human variation in ENTPD1 influences predisposition to diabetes or diabetic nephropathy. We analyzed ENTPD1 single nucleotide polymorphisms (SNPs) in 363 African American control subjects, 380 subjects...
Article
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Vascular smooth muscle cell (VSMC) migration and proliferation are critical steps in the pathogenesis of atherosclerosis, post-angioplasty restenosis, neointimal hyperplasia, and chronic allograft rejection. Extracellular nucleotides are known to influence both migration and proliferation of VSMC. Although it is well established that vascular endot...
Article
Signalling actions of extracellular nucleotides via P2 receptors influence cellular function in most tissues. In the inner ear, P2 receptor signaling is involved in many processes including the regulation of hearing sensitivity and the cochlea's response to noise stress. CD39 (NTPDase1/ENTPD1) is an ectonucleotidase (ecto-nucleoside triphosphate di...
Article
Unlabelled: Concanavalin A (Con A)-induced injury is an established natural killer T (NKT) cell-mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A-stimulated cells and bind to specific purinergic type 2 receptors to modulate immune a...
Article
Little is known about how endothelial cells respond to injury, regulate hepatocyte turnover and reconstitute the hepatic vasculature. We aimed to determine the effects of the vascular ectonucleotidase CD39 on sinusoidal endothelial cell responses following partial hepatectomy and to dissect purinergic and growth factor interactions in this model. P...
Article
In this study, we investigate whether the combination of HVJ-AVE liposome-mediated TFPI gene transfer and recombinant TFPI (rTFPI) irrigation would reduce restenosis safely and more effectively. The results indicated that at 4 weeks after angioplasty, the MLD, EELA, IELA and LA of TFPI group and rTFPI group were markedly greater than those of the c...
Article
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Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type 2 purinergic (P2) receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ectoenzyme that hydrolyzes ex...
Article
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Studies in mice with null mutations of adenosine 1 receptor or ecto-5'-nucleotidase genes suggest a critical role of adenosine and its precursor 5'-AMP in tubulovascular signaling. To assess whether the source of juxtaglomerular nucleotides can be traced back to ATP dephosphorylation, experiments were performed in mice with a deficiency in NTPDase1...
Article
Microglia is activated by brain injury. They migrate in response to ATP and although adenosine alone has no effect on wild type microglial migration, we show that inhibition of adenosine receptors impedes ATP triggered migration. CD39 is the dominant cellular ectonucleotidase that degrades nucleotides to nucleosides, including adenosine. Importantl...
Article
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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and ectonucleotidases i. e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/CD39 has been shown to critically modulate levels of circulating nucleotides. This process...
Article
Extracellular nucleotides are released from injured cells and bind purinergic-type 2 receptors (P2-Rs) that modulate inflammatory responses. Ectonucleotidases, such as CD39/nucleoside triphosphate diphosphohydrolase-1, hydrolyze extracellular nucleotides to integrate purinergic signaling responses. Because the role of extracellular nucleotides and...
Article
CD39/ecto-nucleoside triphosphate diphosphohydrolase-type-1 (ENTPD1) is the dominant vascular ecto-nucleotidase that catalyzes the phosphohydrolysis of extracellular nucleotides in the blood and extracellular space. This ecto-enzymatic process modulates endothelial cell, leukocyte, and platelet purinergic receptor-mediated responses to extracellula...
Article
Full-text available
Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute model...
Article
Transplantation exposes vascularized grafts to several potential injuries, including ischemia-reperfusion injury and rejection. These processes are associated with, at least in part, extracellular nucleotide-triggered (type 2 purinergic receptor) inflammatory responses that if left unchecked might compromise the long-term function and survival of t...
Article
Extracellular nucleotide P2-receptor-mediated effects on platelets, leukocytes and endothelium are modulated by ecto-nucleotidases. These ecto-enzymes hydrolyze extracellular nucleotides to the respective nucleosides. The dominant ecto-nucleotidase expressed by the endothelium, by monocytes and vascular smooth muscle cells is CD39/NTPDase1. Ecto-nu...
Article
Transplantation results in exposure of the graft vasculature to warm and cold ischemia, followed by perfusion by circulating blood constituents and obligatory oxidant stress. Further graft injury occurs as consequences of acute humoral cellular rejection or chronic transplant vasculopathy, or both. Extracellular nucleotide stimulation of purinergic...
Article
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Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post-angioplasty stenosis, cerebral ischaemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with organ or cell transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important...
Article
Full-text available
CD39 (ecto-nucleoside triphosphate diphosphohydrolase-1; E-NTPDase-1), is highly expressed on quiescent vascular endothelial cells and efficiently hydrolyzes extracellular ATP and ADP to AMP and ultimately adenosine. This action blocks extracellular nucleotide-dependent platelet aggregation and abrogates endothelial cell activation. However, CD39 e...
Article
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Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endo...
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Endothelial cell production of anticoagulant heparan sulfate (HS(act)) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1). In vitro, HS(act) dramatically enhances the neutralization of coagulation proteases by antithrombin. The in vivo role of HS(act) was evaluated by generating...
Article
Tissue factor pathway inhibitor (TFPI), as a primary inhibitor of TF-induced coagulation, reduces neointimal formation and luminal stenosis by inhibiting coagulation and thrombosis after vessel wall injury. Here, we investigated the effect of TFPI gene delivery with a HVJ-AVE liposome vector on restenosis in atherosclerotic arteries after angioplas...
Article
Full-text available
CD39, the endothelial ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), regulates vascular inflammation and thrombosis by hydrolyzing ATP and ADP. Although ecto-NTPDase activities have been used as a marker of epidermal dendritic cells (DCs) known as Langerhans cells, the identity and function of these activities remain unknown. Here we re...
Article
Extracellular nucleotide stimulation of purinergic/pyrimidinergic type-2 (P2) receptors are components of platelet, endothelial cell (EC), and leukocyte activation that culminate in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (or NTPDase-1), is highly expressed on quiescent endotheliu...
Article
Extracellular nucleotides are ubiquitous extracellular mediators that interact with and activate nucleotide type 2 (P2) receptors. These receptors initiate a wide variety of signalling pathways that appear important for functional associations between neurons and glial cells and for the regulation of blood flow, haemostatic and inflammatory reactio...
Article
Beta-2 glycoprotein I is a plasma protein with the ability to bind with various kinds of negatively charged substances. The complete amino acid sequence and the location of all the disulfide bonds of bovine beta-2 glycoprotein I were determined. Bovine beta-2 glycoprotein I consists of 326 amino acid residues with five asparagine-linked carbohydrat...

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