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Current Protein & Peptide Science

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ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

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Review Article

Anti-Platelet Peptides Targeting αIIbβ3 Outside-In Signaling Pathway

Author(s): Jialing Wang and Xin Xu*

Volume 24, Issue 1, 2023

Published on: 15 December, 2022

Page: [31 - 42] Pages: 12

DOI: 10.2174/1389203724666221114113413

Price: $65

Abstract

Platelets and their progenitors express high levels of integrin αIIbβ3, which plays a key role in platelet functions, hemostasis, and arterial thrombosis. Because of their quick and high efficacy, the three anti-αIIbβ3 drugs, abciximab, eptifibatide, and tirofiban, are regarded as potent anti-thrombotics and clinically approved by US Food and Drug Administration. However, because they interfere with the inside-out signaling of αIIbβ3, which is required for stable platelet adhesion and aggregation, the application of abciximab, eptifibatide, and tirofiban is restricted to patients undergoing percutaneous coronary intervention. On the other hand, the outside-in signaling of αIIbβ3 in platelets appears to be responsible for thrombus stabilization, and selective interference with the propagation of outside-in signals might signify a new therapeutic strategy to preferentially inhibit platelet-rich arterial thrombosis with less bleeding issues caused by way of compromised major hemostasis. The purpose of this review is to describe the bidirectional signal transduction of integrin αIIbβ3 in platelets with a focus on outside-in signaling, more efficient and safer anti-αIIbβ3 peptides, and the potential drug targets for future anti-platelet research.

Keywords: Platelet, peptides, αIIbβ3, bidirectional signal, outside-in signaling, arterial thrombosis, bleeding.

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[1]
Kulkarni, S.; Dopheide, S.M.; Yap, C.L.; Ravanat, C.; Freund, M.; Mangin, P.; Heel, K.A.; Street, A.; Harper, I.S.; Lanza, F.; Jackson, S.P. A revised model of platelet aggregation. J. Clin. Invest., 2000, 105(6), 783-791.
[http://dx.doi.org/10.1172/JCI7569] [PMID: 10727447]
[2]
Wang, Y.; Zhao, Y.; Sun, R.; Kong, W.; Wang, B.; Yang, G.; Li, Y. Discovery of novel antagonists of glycoprotein IIb/IIIa-mediated plate-let aggregation through virtual screening. Bioorg. Med. Chem. Lett., 2015, 25(6), 1249-1253.
[http://dx.doi.org/10.1016/j.bmcl.2015.01.053] [PMID: 25677660]
[3]
George, J.N.; Caen, J.P.; Nurden, A.T. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood, 1990, 75(7), 1383-1395.
[http://dx.doi.org/10.1182/blood.V75.7.1383.1383] [PMID: 2180491]
[4]
Bury, L.; Zetterberg, E.; Leinøe, E.B.; Falcinelli, E.; Marturano, A.; Manni, G.; Nurden, A.T.; Gresele, P. A novel variant Glanzmann thrombasthenia due to co-inheritance of a loss- and a gain-of-function mutation of ITGB3: evidence of a dominant effect of gain-of-function mutations. Haematologica, 2018, 103(6), e259-e263.
[http://dx.doi.org/10.3324/haematol.2017.180927] [PMID: 29439184]
[5]
Zhou, L.; Jiang, M.; Shen, H.; You, T.; Ding, Z.; Cui, Q.; Ma, Z.; Yang, F.; Xie, Z.; Shi, H.; Su, J.; Cao, L.; Lin, J.; Yin, J.; Dai, L.; Wang, H.; Wang, Z.; Yu, Z.; Ruan, C.; Xia, L. Clinical and molecular insights into Glanzmann’s thrombasthenia in China. Clin. Genet., 2018, 94(2), 213-220.
[http://dx.doi.org/10.1111/cge.13366] [PMID: 29675921]
[6]
Qiao, J.; Wu, X.; Luo, Q.; Wei, G.; Xu, M.; Wu, Y.; Liu, Y.; Li, X.; Zi, J.; Ju, W.; Fu, L.; Chen, C.; Wu, Q.; Zhu, S.; Qi, K.; Li, D.; Li, Z.; Andrews, R.K.; Zeng, L.; Gardiner, E.E.; Xu, K. NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis. Haematologica, 2018, 103(9), 1568-1576.
[http://dx.doi.org/10.3324/haematol.2018.191700] [PMID: 29794149]
[7]
Mehrbod, M.; Trisno, S.; Mofrad, M.R.K. On the activation of integrin αIIbβ3: outside-in and inside-out pathways. Biophys. J., 2013, 105(6), 1304-1315.
[http://dx.doi.org/10.1016/j.bpj.2013.07.055] [PMID: 24047981]
[8]
Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; Das, S.R.; de Ferranti, S.; Després, J.P.; Fullerton, H.J.; Howard, V.J.; Huffman, M.D.; Isasi, C.R.; Jiménez, M.C.; Judd, S.E.; Kissela, B.M.; Lichtman, J.H.; Lisabeth, L.D.; Liu, S.; Mackey, R.H.; Magid, D.J.; McGuire, D.K.; Mohler, E.R., III; Moy, C.S.; Muntner, P.; Mussolino, M.E.; Nasir, K.; Neumar, R.W.; Nichol, G.; Palaniappan, L.; Pandey, D.K.; Reeves, M.J.; Rodriguez, C.J.; Rosamond, W.; Sorlie, P.D.; Stein, J.; Towfighi, A.; Turan, T.N.; Virani, S.S.; Woo, D.; Yeh, R.W.; Turner, M.B. American Heart Association Statistics Committee. Stroke Statistics Subcommittee.; Writing Group Members. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation, 2016, 133(4), e38-e360.
[http://dx.doi.org/10.1161/CIR.0000000000000350] [PMID: 26673558]
[9]
Bury, L.; Malara, A.; Gresele, P.; Balduini, A. Outside-in signalling generated by a constitutively activated integrin αIIbβ3 impairs pro-platelet formation in human megakaryocytes. PLoS One, 2012, 7(4), e34449.
[http://dx.doi.org/10.1371/journal.pone.0034449] [PMID: 22539947]
[10]
McNicol, A.; Israels, S.J. Platelets and anti-platelet therapy. J. Pharmacol. Sci., 2003, 93(4), 381-396.
[http://dx.doi.org/10.1254/jphs.93.381] [PMID: 14737006]
[11]
Bosch, X.; Marrugat, J.; Sanchis, J. Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes. Cochrane Database Syst. Rev., 2013, (10), CD002130.
[http://dx.doi.org/10.1002/14651858.CD002130.pub3] [PMID: 24136036]
[12]
Bougie, D.W.; Wilker, P.R.; Wuitschick, E.D.; Curtis, B.R.; Malik, M.; Levine, S.; Lind, R.N.; Pereira, J.; Aster, R.H. Acute thrombocyto-penia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood, 2002, 100(6), 2071-2076.
[http://dx.doi.org/10.1182/blood.V100.6.2071] [PMID: 12200368]
[13]
Scirica, B.M.; Cannon, C.P.; Cooper, R.; Aster, R.H.; Brassard, J.; McCabe, C.H.; Charlesworth, A.; Skene, A.M.; Braunwald, E. Drug-induced thrombocytopenia and thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Pa-tients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial. J. Thromb. Thrombolysis, 2006, 22(2), 95-102.
[http://dx.doi.org/10.1007/s11239-006-8669-4] [PMID: 17008974]
[14]
Gao, C.; Boylan, B.; Bougie, D.; Gill, J.C.; Birenbaum, J.; Newman, D.K.; Aster, R.H.; Newman, P.J. Eptifibatide-induced thrombocytope-nia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain. J. Clin. Invest., 2009, 119(3), 504-511.
[http://dx.doi.org/10.1172/JCI36745] [PMID: 19197137]
[15]
Chong, B.H. Drug-induced thrombocytopenia: MIBS trumps LIBS. Blood, 2012, 119(26), 6177-6178.
[http://dx.doi.org/10.1182/blood-2012-04-423939] [PMID: 22745292]
[16]
Bougie, D.W.; Rasmussen, M.; Zhu, J.; Aster, R.H. Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin. Blood, 2012, 119(26), 6317-6325.
[http://dx.doi.org/10.1182/blood-2012-01-406322] [PMID: 22490676]
[17]
Shen, B.; Zhao, X.; O’Brien, K.A.; Stojanovic-Terpo, A.; Delaney, M.K.; Kim, K.; Cho, J.; Lam, S.C.T.; Du, X. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature, 2013, 503(7474), 131-135.
[http://dx.doi.org/10.1038/nature12613] [PMID: 24162846]
[18]
Zhu, J.; Zhu, J.; Negri, A.; Provasi, D.; Filizola, M.; Coller, B.S.; Springer, T.A. Closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specific antagonist that does not induce opening. Blood, 2010, 116(23), 5050-5059.
[http://dx.doi.org/10.1182/blood-2010-04-281154] [PMID: 20679525]
[19]
Tadokoro, S.; Shattil, S.J.; Eto, K.; Tai, V.; Liddington, R.C.; de Pereda, J.M.; Ginsberg, M.H.; Calderwood, D.A. Talin binding to integrin beta tails: a final common step in integrin activation. Science, 2003, 302(5642), 103-106.
[http://dx.doi.org/10.1126/science.1086652] [PMID: 14526080]
[20]
Ye, F.; Kim, C.; Ginsberg, M.H. Molecular mechanism of insideout integrin regulation. J Thromb Haemost., 2011, 9 Suppl 1(01), 20-25.
[http://dx.doi.org/10.1111/j.1538-7836.2011.04355.x] [PMID: 21781238]
[21]
Gong, H.; Shen, B.; Flevaris, P.; Chow, C.; Lam, S.C.T.; Voyno-Yasenetskaya, T.A.; Kozasa, T.; Du, X. G protein subunit Galpha13 binds to integrin alphaIIbbeta3 and mediates integrin “outside-in” signaling. Science, 2010, 327(5963), 340-343.
[http://dx.doi.org/10.1126/science.1174779] [PMID: 20075254]
[22]
Shen, B.; Delaney, M.K.; Du, X. Inside-out, outside-in, and inside–outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr. Opin. Cell Biol., 2012, 24(5), 600-606.
[http://dx.doi.org/10.1016/j.ceb.2012.08.011] [PMID: 22980731]
[23]
Bye, A.P.; Unsworth, A.J.; Gibbins, J.M. Platelet signaling: a complex interplay between inhibitory and activatory networks. J. Thromb. Haemost., 2016, 14(5), 918-930.
[http://dx.doi.org/10.1111/jth.13302] [PMID: 26929147]
[24]
Hynes, R.O. Integrins. Cell, 2002, 110(6), 673-687.
[http://dx.doi.org/10.1016/S0092-8674(02)00971-6] [PMID: 12297042]
[25]
Li, Z.; Delaney, M.K.; O’Brien, K.A.; Du, X. Signaling during platelet adhesion and activation. Arterioscler. Thromb. Vasc. Biol., 2010, 30(12), 2341-2349.
[http://dx.doi.org/10.1161/ATVBAHA.110.207522] [PMID: 21071698]
[26]
Wegener, K.L.; Partridge, A.W.; Han, J.; Pickford, A.R.; Liddington, R.C.; Ginsberg, M.H.; Campbell, I.D. Structural basis of integrin acti-vation by talin. Cell, 2007, 128(1), 171-182.
[http://dx.doi.org/10.1016/j.cell.2006.10.048] [PMID: 17218263]
[27]
Nieswandt, B.; Varga-Szabo, D.; Elvers, M. Integrins in platelet activation. J. Thromb. Haemost., 2009, 7(Suppl. 1), 206-209.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03370.x] [PMID: 19630801]
[28]
Ma, Y.Q.; Qin, J.; Wu, C.; Plow, E.F. Kindlin-2 (Mig-2): a co-activator of β3 integrins. J. Cell Biol., 2008, 181(3), 439-446.
[http://dx.doi.org/10.1083/jcb.200710196] [PMID: 18458155]
[29]
Moser, M.; Nieswandt, B.; Ussar, S.; Pozgajova, M.; Fässler, R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat. Med., 2008, 14(3), 325-330.
[http://dx.doi.org/10.1038/nm1722] [PMID: 18278053]
[30]
Durrant, T.N.; van den Bosch, M.T.; Hers, I. Integrin αIIbβ3 outside-in signaling. Blood, 2017, 130(14), 1607-1619.
[http://dx.doi.org/10.1182/blood-2017-03-773614] [PMID: 28794070]
[31]
Buensuceso, C.S.; Arias-Salgado, E.G.; Shattil, S.J. Protein-protein interactions in platelet alphaIIbbeta3 signaling. Semin. Thromb. Hemost., 2004, 30(4), 427-439.
[http://dx.doi.org/10.1055/s-2004-833478] [PMID: 15354264]
[32]
Martin, V.; Guillermet-Guibert, J.; Chicanne, G.; Cabou, C.; Jandrot-Perrus, M.; Plantavid, M.; Vanhaesebroeck, B.; Payrastre, B.; Grata-cap, M.P. Deletion of the p110β isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood, 2010, 115(10), 2008-2013.
[http://dx.doi.org/10.1182/blood-2009-04-217224] [PMID: 20065293]
[33]
Canobbio, I.; Stefanini, L.; Cipolla, L.; Ciraolo, E.; Gruppi, C.; Balduini, C.; Hirsch, E.; Torti, M. Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets. Blood, 2009, 114(10), 2193-2196.
[http://dx.doi.org/10.1182/blood-2009-03-208074] [PMID: 19515725]
[34]
Das, M.; Subbayya Ithychanda, S.; Qin, J.; Plow, E.F. Mechanisms of talin-dependent integrin signaling and crosstalk. Biochim. Biophys. Acta Biomembr., 2014, 1838(2), 579-588.
[http://dx.doi.org/10.1016/j.bbamem.2013.07.017] [PMID: 23891718]
[35]
Huang, T.F.; Sheu, J.R.; Teng, C.M.; Chen, S.W.; Liu, C.S. Triflavin, an antiplatelet Arg-Gly-Asp-containing peptide, is a specific antagonist of platelet membrane glycoprotein IIb-IIIa complex. J. Biochem., 1991, 109(2), 328-334.
[PMID: 1864844]
[36]
Kuo, Y.J.; Chung, C.H.; Huang, T.F. From discovery of snake venom disintegrins to a safer therapeutic antithrombotic agent. Toxins (Basel), 2019, 11(7), 372.
[http://dx.doi.org/10.3390/toxins11070372] [PMID: 31247995]
[37]
Schwarz, M.; Meade, G.; Stoll, P.; Ylanne, J.; Bassler, N.; Chen, Y.C.; Hagemeyer, C.E.; Ahrens, I.; Moran, N.; Kenny, D.; Fitzgerald, D.; Bode, C.; Peter, K. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ. Res., 2006, 99(1), 25-33.
[http://dx.doi.org/10.1161/01.RES.0000232317.84122.0c] [PMID: 16778135]
[38]
Schwarz, M.; Röttgen, P.; Takada, Y.; Gall, F.L.; Knackmuss, S.; Bassler, N.; Büttner, C.; Little, M.; Bode, C.; Peter, K. Single‐chain antibodies for the conformation‐specific blockade of activated platelet integrin α IIb β 3 designed by subtractive selection from naïve human phage libraries. FASEB J., 2004, 18(14), 1704-1706.
[http://dx.doi.org/10.1096/fj.04-1513fje] [PMID: 15522915]
[39]
Armstrong, P.C.; Peter, K. GPIIb/IIIa inhibitors: From bench to bedside and back to bench again. Thromb. Haemost., 2012, 107(5), 808-814.
[http://dx.doi.org/10.1160/TH11-10-0727] [PMID: 22370973]
[40]
Reheman, A.; Xu, X.; Reddy, E.C.; Ni, H. Targeting activated platelets and fibrinolysis: hitting two birds with one stone. Circ. Res., 2014, 114(7), 1070-1073.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.303600] [PMID: 24677231]
[41]
Kouki, A.; Mitsios, J.V.; Sakarellos-Daitsiotis, M.; Sakarellos, C.; Tselepis, A.D.; Tsikaris, V.; Tsoukatos, D.C. Highly constrained cyclic (S,S) -CXaaC- peptides as inhibitors of fibrinogen binding to platelets. J. Thromb. Haemost., 2005, 3(10), 2324-2330.
[http://dx.doi.org/10.1111/j.1538-7836.2005.01487.x] [PMID: 16129021]
[42]
Roussa, V.D.; Stathopoulou, E.M.; Papamichael, N.D.; Englezopoulos, C.V.; Rousouli, K.I.; Trypou, P.; Moussis, V.; Tellis, C.C.; Katsouras, C.S.; Tsikaris, V.; Tselepis, A.D.; Michalis, L.K. A highly constrained cyclic (S,S)-CDC- peptide is a potent inhibitor of carotid artery thrombosis in rabbits. Platelets, 2011, 22(5), 361-370.
[http://dx.doi.org/10.3109/09537104.2010.531795] [PMID: 21158497]
[43]
Kong, Y.; Huo, J.; Xu, W.; Xiong, J.; Li, Y.; Wu, W. A novel anti-platelet aggregation tripeptide from Agkistrodon acutus venom: Isolation and characterization. Toxicon, 2009, 54(2), 103-109.
[http://dx.doi.org/10.1016/j.toxicon.2009.03.027] [PMID: 19345702]
[44]
Kong, Y.; Wang, Y.; Yang, W.; Xie, Z.; Li, Z. LX0702, a novel snake venom peptide derivative, inhibits thrombus formation via affecting the binding of fibrinogen with GPIIb/IIIa. J. Pharmacol. Sci., 2015, 127(4), 462-466.
[http://dx.doi.org/10.1016/j.jphs.2015.03.010] [PMID: 25913760]
[45]
Vowinkel, T.; Mori, M.; Krieglstein, C.F.; Russell, J.; Saijo, F.; Bharwani, S.; Turnage, R.H.; Davidson, W.S.; Tso, P.; Granger, D.N.; Kalogeris, T.J. Apolipoprotein A-IV inhibits experimental colitis. J. Clin. Invest., 2004, 114(2), 260-269.
[http://dx.doi.org/10.1172/JCI200421233] [PMID: 15254593]
[46]
Wang, F.; Kohan, A.B.; Lo, C.M.; Liu, M.; Howles, P.; Tso, P. Apolipoprotein A-IV: a protein intimately involved in metabolism. J. Lipid Res., 2015, 56(8), 1403-1418.
[http://dx.doi.org/10.1194/jlr.R052753] [PMID: 25640749]
[47]
Kronenberg, F.; Stühlinger, M.; Trenkwalder, E.; Geethanjali, F.S.; Pachinger, O.; von Eckardstein, A.; Dieplinger, H. Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease. J. Am. Coll. Cardiol., 2000, 36(3), 751-757.
[http://dx.doi.org/10.1016/S0735-1097(00)00775-0] [PMID: 10987595]
[48]
Wong, W.R.; Hawe, E.; Li, L.K.; Miller, G.J.; Nicaud, V.; Pennacchio, L.A.; Humphries, S.E.; Talmud, P.J. Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels. Circ. Res., 2003, 92(9), 969-975.
[http://dx.doi.org/10.1161/01.RES.0000069688.94567.7A] [PMID: 12676816]
[49]
Kretowski, A.; Hokanson, J.E.; McFann, K.; Kinney, G.L.; Snell-Bergeon, J.K.; Maahs, D.M.; Wadwa, R.P.; Eckel, R.H.; Ogden, L.G.; Garg, S.K.; Li, J.; Cheng, S.; Erlich, H.A.; Rewers, M. The apolipoprotein A-IV Gln360His polymorphism predicts progression of coro-nary artery calcification in patients with type 1 diabetes. Diabetologia, 2006, 49(8), 1946-1954.
[http://dx.doi.org/10.1007/s00125-006-0317-1] [PMID: 16770585]
[50]
Xu, X.R.; Wang, Y.; Adili, R.; Ju, L.; Spring, C.M.; Jin, J.W.; Yang, H.; Neves, M.A.D.; Chen, P.; Yang, Y.; Lei, X.; Chen, Y.; Gallant, R.C.; Xu, M.; Zhang, H.; Song, J.; Ke, P.; Zhang, D.; Carrim, N.; Yu, S.Y.; Zhu, G.; She, Y.M.; Cyr, T.; Fu, W.; Liu, G.; Connelly, P.W.; Rand, M.L.; Adeli, K.; Freedman, J.; Lee, J.E.; Tso, P.; Marchese, P.; Davidson, W.S.; Jackson, S.P.; Zhu, C.; Ruggeri, Z.M.; Ni, H. Apolipopro-tein A-IV binds αIIbβ3 integrin and inhibits thrombosis. Nat. Commun., 2018, 9(1), 3608.
[http://dx.doi.org/10.1038/s41467-018-05806-0] [PMID: 30190457]
[51]
Hao, X.; Tang, X.; Luo, L.; Wang, Y.; Lai, R.; Lu, Q. A novel ranacyclin-like peptide with anti-platelet activity identified from skin secretions of the frog Amolops loloensis. Gene, 2016, 576(1), 171-175.
[http://dx.doi.org/10.1016/j.gene.2015.10.003] [PMID: 26449399]
[52]
Shen, C.; Liu, M.; Tian, H.; Li, J.; Xu, R.; Mwangi, J.; Lu, Q.; Hao, X.; Lai, R. Conformation-Specific Blockade of αIIbβ3 by a Non-RGD Peptide to Inhibit Platelet Activation without Causing Significant Bleeding and Thrombocytopenia. Thromb. Haemost., 2020, 120(10), 1432-1441.
[http://dx.doi.org/10.1055/s-0040-1714215] [PMID: 32717755]
[53]
Zhu, G.; Zhang, Q.; Reddy, E.C.; Carrim, N.; Chen, Y.; Xu, X.R.; Xu, M.; Wang, Y.; Hou, Y.; Ma, L.; Li, Y.; Rui, M.; Petruzziello-Pellegrini, T.N.; Lavalle, C.; Stratton, T.W.; Lei, X.; Adili, R.; Chen, P.; Zhu, C.; Wilkins, J.A.; Hynes, R.O.; Freedman, J.; Ni, H. The integrin PSI domain has an endogenous thiol isomerase function and is a novel target for antiplatelet therapy. Blood, 2017, 129(13), 1840-1854.
[http://dx.doi.org/10.1182/blood-2016-07-729400] [PMID: 28122739]
[54]
Jordan, P.A.; Stevens, J.M.; Hubbard, G.P.; Barrett, N.E.; Sage, T.; Authi, K.S.; Gibbins, J.M. A role for the thiol isomerase protein ERP5 in platelet function. Blood, 2005, 105(4), 1500-1507.
[http://dx.doi.org/10.1182/blood-2004-02-0608] [PMID: 15466936]
[55]
Robinson, A.; O’Neill, S.; Kiernan, A.; O’Donoghue, N.; Moran, N. Bacitracin reveals a role for multiple thiol isomerases in platelet func-tion. Br. J. Haematol., 2006, 132(3), 339-348.
[http://dx.doi.org/10.1111/j.1365-2141.2005.05878.x] [PMID: 16409299]
[56]
Holbrook, L.M.; Watkins, N.A.; Simmonds, A.D.; Jones, C.I.; Ouwehand, W.H.; Gibbins, J.M. Platelets release novel thiol isomerase en-zymes which are recruited to the cell surface following activation. Br. J. Haematol., 2010, 148(4), 627-637.
[http://dx.doi.org/10.1111/j.1365-2141.2009.07994.x] [PMID: 19995400]
[57]
Wu, Y.; Ahmad, S.S.; Zhou, J.; Wang, L.; Cully, M.P.; Essex, D.W. The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis. Blood, 2012, 119(7), 1737-1746.
[http://dx.doi.org/10.1182/blood-2011-06-360685] [PMID: 22207737]
[58]
Wang, L.; Wu, Y.; Zhou, J.; Ahmad, S.S.; Mutus, B.; Garbi, N.; Hämmerling, G.; Liu, J.; Essex, D.W. Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin. Blood, 2013, 122(22), 3642-3650.
[http://dx.doi.org/10.1182/blood-2013-06-506691] [PMID: 24030382]
[59]
O’Neill, S.; Robinson, A.; Deering, A.; Ryan, M.; Fitzgerald, D.J.; Moran, N. The platelet integrin alpha IIbbeta 3 has an endogenous thiol isomerase activity. J. Biol. Chem., 2000, 275(47), 36984-36990.
[http://dx.doi.org/10.1074/jbc.M003279200] [PMID: 10942760]
[60]
Lahav, J.; Jurk, K.; Hess, O.; Barnes, M.J.; Farndale, R.W.; Luboshitz, J.; Kehrel, B.E. Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange. Blood, 2002, 100(7), 2472-2478.
[http://dx.doi.org/10.1182/blood-2001-12-0339] [PMID: 12239158]
[61]
Stoll, P.; Bassler, N.; Hagemeyer, C.E.; Eisenhardt, S.U.; Chen, Y.C.; Schmidt, R.; Schwarz, M.; Ahrens, I.; Katagiri, Y.; Pannen, B.; Bode, C.; Peter, K. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscler. Thromb. Vasc. Biol., 2007, 27(5), 1206-1212.
[http://dx.doi.org/10.1161/ATVBAHA.106.138875] [PMID: 17322097]
[62]
Hohmann, J.D.; Wang, X.; Krajewski, S.; Selan, C.; Haller, C.A.; Straub, A.; Chaikof, E.L.; Nandurkar, H.H.; Hagemeyer, C.E.; Peter, K. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood, 2013, 121(16), 3067-3075.
[http://dx.doi.org/10.1182/blood-2012-08-449694] [PMID: 23380744]
[63]
Bonnard, T.; Tennant, Z.; Niego, B.E.; Kanojia, R.; Alt, K.; Jagdale, S.; Law, L.S.; Rigby, S.; Medcalf, R.L.; Peter, K.; Hagemeyer, C.E. Novel thrombolytic drug based on thrombin cleavable microplasminogen coupled to a single‐chain antibody specific for activated GPIIb/IIIa. J. Am. Heart Assoc., 2017, 6(2), e004535.
[http://dx.doi.org/10.1161/JAHA.116.004535] [PMID: 28159824]
[64]
Topcic, D.; Kim, W.; Holien, J.K.; Jia, F.; Armstrong, P.C.; Hohmann, J.D.; Straub, A.; Krippner, G.; Haller, C.A.; Domeij, H.; Hagemeyer, C.E.; Parker, M.W.; Chaikof, E.L.; Peter, K. An activation-specific platelet inhibitor that can be turned on/off by medically used hypo-thermia. Arterioscler. Thromb. Vasc. Biol., 2011, 31(9), 2015-2023.
[http://dx.doi.org/10.1161/ATVBAHA.111.226241] [PMID: 21659646]
[65]
Kuo, Y.J.; Chung, C.H.; Pan, T.Y.; Chuang, W.J.; Huang, T.F. A novel αIIbβ3 antagonist from snake venom prevents thrombosis without causing bleeding. Toxins (Basel), 2019, 12(1), 11.
[http://dx.doi.org/10.3390/toxins12010011] [PMID: 31877725]
[66]
Kuo, Y.J.; Chen, Y.R.; Hsu, C.C.; Peng, H.C.; Huang, T.F. An α II b β 3 antagonist prevents thrombosis without causing Fc receptor γ-chain IIa-mediated thrombocytopenia. J. Thromb. Haemost., 2017, 15(11), 2230-2244.
[http://dx.doi.org/10.1111/jth.13803] [PMID: 28815933]
[67]
Shen, C.; Liu, M.; Xu, R.; Wang, G.; Li, J.; Chen, P.; Ma, W.; Mwangi, J.; Lu, Q.; Duan, Z.; Zhang, Z.; Dahmani, F.Z.; Mackeigan, D.T.; Ni, H.; Lai, R. The 14-3-3ζ–c-Src–integrin-β3 complex is vital for platelet activation. Blood, 2020, 136(8), 974-988.
[http://dx.doi.org/10.1182/blood.2019002314] [PMID: 32584951]
[68]
Obergfell, A.; Eto, K.; Mocsai, A.; Buensuceso, C.; Moores, S.L.; Brugge, J.S.; Lowell, C.A.; Shattil, S.J. Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton. J. Cell Biol., 2002, 157(2), 265-275.
[http://dx.doi.org/10.1083/jcb.200112113] [PMID: 11940607]
[69]
Arias-Salgado, E.G.; Lizano, S.; Shattil, S.J.; Ginsberg, M.H. Specification of the direction of adhesive signaling by the integrin beta cyto-plasmic domain. J. Biol. Chem., 2005, 280(33), 29699-29707.
[http://dx.doi.org/10.1074/jbc.M503508200] [PMID: 15937333]
[70]
Flevaris, P.; Stojanovic, A.; Gong, H.; Chishti, A.; Welch, E.; Du, X. A molecular switch that controls cell spreading and retraction. J. Cell Biol., 2007, 179(3), 553-565.
[http://dx.doi.org/10.1083/jcb.200703185] [PMID: 17967945]
[71]
Xi, X.; Bodnar, R.J.; Li, Z.; Lam, S.C.T.; Du, X. Critical roles for the COOH-terminal NITY and RGT sequences of the integrin β3 cyto-plasmic domain in inside-out and outside-in signaling. J. Cell Biol., 2003, 162(2), 329-339.
[http://dx.doi.org/10.1083/jcb.200303120] [PMID: 12860973]
[72]
Su, X.; Mi, J.; Yan, J.; Flevaris, P.; Lu, Y.; Liu, H.; Ruan, Z.; Wang, X.; Kieffer, N.; Chen, S.; Du, X.; Xi, X. RGT, a synthetic peptide cor-responding to the integrin β3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin αIIbβ3 with Src kinase. Blood, 2008, 112(3), 592-602.
[http://dx.doi.org/10.1182/blood-2007-09-110437] [PMID: 18398066]
[73]
Huang, J.; Shi, X.; Xi, W.; Liu, P.; Long, Z.; Xi, X. Evaluation of targeting c-Src by the RGT-containing peptide as a novel antithrombotic strategy. J. Hematol. Oncol., 2015, 8(1), 62.
[http://dx.doi.org/10.1186/s13045-015-0159-8] [PMID: 26025329]
[74]
Harris, J.M.; Chess, R.B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov., 2003, 2(3), 214-221.
[http://dx.doi.org/10.1038/nrd1033] [PMID: 12612647]
[75]
Veronese, F.M.; Pasut, G. PEGylation, successful approach to drug delivery. Drug Discov. Today, 2005, 10(21), 1451-1458.
[http://dx.doi.org/10.1016/S1359-6446(05)03575-0] [PMID: 16243265]
[76]
Bhattarai, N.; Matsen, F.A.; Zhang, M. PEG-grafted chitosan as an injectable thermoreversible hydrogel. Macromol. Biosci., 2005, 5(2), 107-111.
[http://dx.doi.org/10.1002/mabi.200400140] [PMID: 15719428]
[77]
Harris, J.M.; Martin, N.E.; Modi, M. Pegylation. Clin. Pharmacokinet., 2001, 40(7), 539-551.
[http://dx.doi.org/10.2165/00003088-200140070-00005] [PMID: 11510630]
[78]
Youn, Y.S.; Na, D.H.; Yoo, S.D.; Song, S.C.; Lee, K.C. Carbohydrate-specifically polyethylene glycol-modified ricin A-chain with improved therapeutic potential. Int. J. Biochem. Cell Biol., 2005, 37(7), 1525-1533.
[http://dx.doi.org/10.1016/j.biocel.2005.01.014] [PMID: 15833282]
[79]
Hsu, C.C.; Chuang, W.J.; Chung, C.H.; Chang, C.H.; Peng, H.C.; Huang, T.F. Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αIIbβ3 antagonist, disintegrin. Thromb. Res., 2016, 143, 3-10.
[http://dx.doi.org/10.1016/j.thromres.2016.04.020] [PMID: 27161326]
[80]
Kuo, Y.J.; Chang, Y.T.; Chung, C.H.; Chuang, W.J.; Huang, T.F. Improved antithrombotic activity and diminished bleeding side effect of a PEGylated αIIbβ3 antagonist, disintegrin. Toxins (Basel), 2020, 12(7), 426.
[http://dx.doi.org/10.3390/toxins12070426] [PMID: 32605221]
[81]
Hers, I.; Donath, J.; Litjens, P.E.M.H.; van Willigen, G.; Akkerman, J.W.N. Inhibition of platelet integrin alpha(IIb)beta(3) by peptides that interfere with protein kinases and the beta(3) tail. Arterioscler. Thromb. Vasc. Biol., 2000, 20(6), 1651-1660.
[http://dx.doi.org/10.1161/01.ATV.20.6.1651] [PMID: 10845885]
[82]
Litjens, P.E.M.H.; Gorter, G.; Ylänne, J.; Akkerman, J-W.N.; van Willigen, G. Involvement of the beta3 E749ATSTFTN756 region in sta-bilizing integrin alphaIIbbeta3-ligand interaction. J. Thromb. Haemost., 2003, 1(10), 2216-2224.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00394.x] [PMID: 14521607]
[83]
Litjens, P.E.M.H.; Kroner, C.I.; Akkerman, J.W.N.; van Willigen, G. Cytoplasmic regions of the beta3 subunit of integrin alphaIIbbeta3 involved in platelet adhesion on fibrinogen under flow conditions. J. Thromb. Haemost., 2003, 1(9), 2014-2021.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00381.x] [PMID: 12941045]
[84]
Martin, K.; Meade, G.; Moran, N.; Shields, D.C.; Kenny, D. A palmitylated peptide derived from the glycoprotein Ibbeta cytoplasmic tail inhibits platelet activation. J. Thromb. Haemost., 2003, 1(12), 2643-2652.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00478.x] [PMID: 14675101]
[85]
Dai, K.; Bodnar, R.; Berndt, M.C.; Du, X. A critical role for 14-3-3ζ protein in regulating the VWF binding function of platelet glycoprotein Ib-IX and its therapeutic implications. Blood, 2005, 106(6), 1975-1981.
[http://dx.doi.org/10.1182/blood-2005-01-0440] [PMID: 15941906]
[86]
Liu, J.; Jackson, C.W.; Gruppo, R.A.; Jennings, L.K.; Gartner, T.K. The β3 subunit of the integrin αIIbβ3 regulates αIIb-mediated outside-in signaling. Blood, 2005, 105(11), 4345-4352.
[http://dx.doi.org/10.1182/blood-2004-07-2718] [PMID: 15701721]
[87]
Wang, Z.; Leisner, T.M.; Parise, L.V. Platelet α2β1 integrin activation: contribution of ligand internalization and the α2-cytoplasmic domain. Blood, 2003, 102(4), 1307-1315.
[http://dx.doi.org/10.1182/blood-2002-09-2753] [PMID: 12738679]
[88]
Tan, M.L.; Choong, P.F.M.; Dass, C.R. Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery. Peptides, 2010, 31(1), 184-193.
[http://dx.doi.org/10.1016/j.peptides.2009.10.002] [PMID: 19819278]
[89]
Pang, A.; Cheng, N.; Cui, Y.; Bai, Y.; Hong, Z.; Delaney, M.K.; Zhang, Y.; Chang, C.; Wang, C.; Liu, C.; Plata, P.L.; Zakharov, A.; Kabirov, K.; Rehman, J.; Skidgel, R.A.; Malik, A.B.; Liu, Y.; Lyubimov, A.; Gu, M.; Du, X. High-loading Gα 13 -binding EXE peptide nanoparticles prevent thrombosis and protect mice from cardiac ischemia/reperfusion injury. Sci. Transl. Med., 2020, 12(552), eaaz7287.
[http://dx.doi.org/10.1126/scitranslmed.aaz7287] [PMID: 32669423]
[90]
Fitter, S.; Tetaz, T.J.; Berndt, M.C.; Ashman, L.K. Molecular cloning of cDNA encoding a novel platelet-endothelial cell tetra-span antigen, PETA-3. Blood, 1995, 86(4), 1348-1355.
[http://dx.doi.org/10.1182/blood.V86.4.1348.bloodjournal8641348] [PMID: 7632941]
[91]
Sincock, P.M.; Mayrhofer, G.; Ashman, L.K. Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and alpha5beta1 integrin. J. Histochem. Cytochem., 1997, 45(4), 515-525.
[http://dx.doi.org/10.1177/002215549704500404] [PMID: 9111230]
[92]
Wright, M.D.; Geary, S.M.; Fitter, S.; Moseley, G.W.; Lau, L.M.; Sheng, K.C.; Apostolopoulos, V.; Stanley, E.G.; Jackson, D.E.; Ashman, L.K. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol. Cell. Biol., 2004, 24(13), 5978-5988.
[http://dx.doi.org/10.1128/MCB.24.13.5978-5988.2004] [PMID: 15199151]
[93]
Lau, L.M.; Wee, J.L.; Wright, M.D.; Moseley, G.W.; Hogarth, P.M.; Ashman, L.K.; Jackson, D.E. The tetraspanin superfamily member CD151 regulates outside-in integrin αIIbβ3 signaling and platelet function. Blood, 2004, 104(8), 2368-2375.
[http://dx.doi.org/10.1182/blood-2003-12-4430] [PMID: 15226180]
[94]
Orlowski, E.; Chand, R.; Yip, J.; Wong, C.; Goschnick, M.W.; Wright, M.D.; Ashman, L.K.; Jackson, D.E. A platelet tetraspanin superfamily member, CD151, is required for regulation of thrombus growth and stability in vivo. J. Thromb. Haemost., 2009, 7(12), 2074-2084.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03612.x] [PMID: 19740096]
[95]
Makkawi, M.; Moheimani, F.; Alserihi, R.; Howells, D.; Wright, M.; Ashman, L.; Jackson, D.E. A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y12 receptor in platelets. Thromb. Haemost., 2015, 114(11), 1004-1019.
[http://dx.doi.org/10.1160/TH14-11-0967] [PMID: 26245294]
[96]
Huang, C.L.; Cheng, J.C.; Liao, C.H.; Stern, A.; Hsieh, J.T.; Wang, C.H.; Hsu, H.L.; Tseng, C.P. Disabled-2 is a negative regulator of integ-rin alpha(IIb)beta(3)-mediated fibrinogen adhesion and cell signaling. J. Biol. Chem., 2004, 279(40), 42279-42289.
[http://dx.doi.org/10.1074/jbc.M402540200] [PMID: 15280374]
[97]
Huang, C.L.; Cheng, J.C.; Stern, A.; Hsieh, J.T.; Liao, C.H.; Tseng, C.P. Disabled-2 is a novel αIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation. J. Cell Sci., 2006, 119(21), 4420-4430.
[http://dx.doi.org/10.1242/jcs.03195] [PMID: 17074833]
[98]
Tsai, H.J.; Huang, C.L.; Chang, Y.W.; Huang, D.Y.; Lin, C.C.; Cooper, J.A.; Cheng, J.C.; Tseng, C.P. Disabled-2 is required for efficient hemostasis and platelet activation by thrombin in mice. Arterioscler. Thromb. Vasc. Biol., 2014, 34(11), 2404-2412.
[http://dx.doi.org/10.1161/ATVBAHA.114.302602] [PMID: 25212232]
[99]
Tsai, H.J.; Chien, K.Y.; Liao, H.R.; Shih, M.S.; Lin, Y.C.; Chang, Y.W.; Cheng, J.C.; Tseng, C.P. Functional links between Disabled-2 Ser723 phosphorylation and thrombin signaling in human platelets. J. Thromb. Haemost., 2017, 15(10), 2029-2044.
[http://dx.doi.org/10.1111/jth.13785] [PMID: 28876503]
[100]
Tsai, H.J.; Cheng, J.C.; Kao, M.L.; Chiu, H.P.; Chiang, Y.H.; Chen, D.P.; Rau, K.M.; Liao, H.R.; Tseng, C.P. Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2. Cell Biosci., 2021, 11(1), 32.
[http://dx.doi.org/10.1186/s13578-021-00532-5] [PMID: 33557943]
[101]
Cosemans, J.M.E.M.; Van Kruchten, R.; Olieslagers, S.; Schurgers, L.J.; Verheyen, F.K.; Munnix, I.C.A.; Waltenberger, J.; Angelillo-Scherrer, A.; Hoylaerts, M.F.; Carmeliet, P.; Heemskerk, J.W.M. Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization. J. Thromb. Haemost., 2010, 8(8), 1797-1808.
[http://dx.doi.org/10.1111/j.1538-7836.2010.03935.x] [PMID: 20546121]
[102]
Laurance, S.; Lemarié, C.A.; Blostein, M.D. Growth arrest-specific gene 6 (gas6) and vascular hemostasis. Adv. Nutr., 2012, 3(2), 196-203.
[http://dx.doi.org/10.3945/an.111.001826] [PMID: 22516727]
[103]
Nagai, K.; Miyoshi, M.; Kake, T.; Fukushima, N.; Matsuura, M.; Shibata, E.; Yamada, S.; Yoshikawa, K.; Kanayama, H.; Fukawa, T.; Yamaguchi, K.; Izaki, H.; Mima, A.; Abe, N.; Araoka, T.; Murakami, T.; Kishi, F.; Kishi, S.; Tominaga, T.; Moriya, T.; Abe, H.; Doi, T. Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy. PLoS One, 2013, 8(6), e66759.
[http://dx.doi.org/10.1371/journal.pone.0066759] [PMID: 23826128]
[104]
Saller, F.; Burnier, L.; Schapira, M.; Angelillo-Scherrer, A. Role of the growth arrest-specific gene 6 (gas6) product in thrombus stabiliza-tion. Blood Cells Mol. Dis., 2006, 36(3), 373-378.
[http://dx.doi.org/10.1016/j.bcmd.2005.12.038] [PMID: 16564713]
[105]
Angelillo-Scherrer, A.; Burnier, L.; Flores, N.; Savi, P.; DeMol, M.; Schaeffer, P.; Herbert, J.M.; Lemke, G.; Goff, S.P.; Matsushima, G.K.; Earp, H.S.; Vesin, C.; Hoylaerts, M.F.; Plaisance, S.; Collen, D.; Conway, E.M.; Wehrle-Haller, B.; Carmeliet, P. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J. Clin. Invest., 2005, 115(2), 237-246.
[http://dx.doi.org/10.1172/JCI22079] [PMID: 15650770]
[106]
Gould, W.R.; Baxi, S.M.; Schroeder, R.; Peng, Y.W.; Leadley, R.J.; Peterson, J.T.; Perrin, L.A. Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J. Thromb. Haemost., 2005, 3(4), 733-741.
[http://dx.doi.org/10.1111/j.1538-7836.2005.01186.x] [PMID: 15733062]
[107]
Law, L.A.; Graham, D.K.; Di Paola, J.; Branchford, B.R. GAS6/TAM pathway signaling in hemostasis and thrombosis. Front. Med. (Lausanne), 2018, 5, 137.
[http://dx.doi.org/10.3389/fmed.2018.00137] [PMID: 29868590]
[108]
Naik, M.U.; Caplan, J.L.; Naik, U.P. Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c–Src complex. Blood, 2014, 123(9), 1393-1402.
[http://dx.doi.org/10.1182/blood-2013-04-496232] [PMID: 24300854]
[109]
Naik, M.U.; Stalker, T.J.; Brass, L.F.; Naik, U.P. JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets. Blood, 2012, 119(14), 3352-3360.
[http://dx.doi.org/10.1182/blood-2011-12-397398] [PMID: 22271446]
[110]
Senis, Y.A.; Antrobus, R.; Severin, S.; Parguiña, A.F.; Rosa, I.; Zitzmann, N.; Watson, S.P.; García, A. Proteomic analysis of integrin al-phaIIbbeta3 outside-in signaling reveals Src-kinase-independent phosphorylation of Dok-1 and Dok-3 leading to SHIP-1 interactions. J. Thromb. Haemost., 2009, 7(10), 1718-1726.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03565.x] [PMID: 19682241]
[111]
Niki, M.; Nayak, M.K.; Jin, H.; Bhasin, N.; Plow, E.F.; Pandolfi, P.P.; Rothman, P.B.; Chauhan, A.K.; Lentz, S.R. Dok-1 negatively regu-lates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice. Thromb. Haemost., 2016, 115(5), 969-978.
[http://dx.doi.org/10.1160/TH15-05-0373] [PMID: 26790499]
[112]
Hughan, S.C.; Spring, C.M.; Schoenwaelder, S.M.; Sturgeon, S.; Alwis, I.; Yuan, Y.; McFadyen, J.D.; Westein, E.; Goddard, D.; Ono, A.; Yamanashi, Y.; Nesbitt, W.S.; Jackson, S.P. Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin αIIbβ3 in mice. J. Biol. Chem., 2014, 289(8), 5051-5060.
[http://dx.doi.org/10.1074/jbc.M113.520148] [PMID: 24385425]

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