Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Selective Activation of G Protein-coupled Estrogen Receptor 1 Attenuates Atherosclerosis

Author(s): Mohammad Zulqurnain Haider, Amirhossein Sahebkar and Ali H. Eid*

Volume 31, Issue 27, 2024

Published on: 12 July, 2023

Page: [4312 - 4319] Pages: 8

DOI: 10.2174/0929867330666230501231528

Price: $65

Abstract

Atherosclerosis remains a leading contributor to cardiovascular disease-associated morbidity and mortality. Interestingly, atherosclerosis-associated mortality rate is higher in men than women. This suggested a protective role for estrogen in the cardiovasculature. These effects of estrogen were initially thought to be mediated by the classic estrogen receptors, ER alpha, and beta. However, genetic knockdown of these receptors did not abolish estrogen’s vasculoprotective effects suggesting that the other membranous Gprotein coupled estrogen receptor, GPER1, maybe the actual mediator. Indeed, in addition to its role in vasotone regulation, this GPER1 appears to play important roles in regulating vascular smooth cell phenotype, a critical player in the onset of atherosclerosis. Moreover, GPER1-selective agonists appear to reduce LDL levels by promoting the expression of LDL receptors as well as potentiating LDL re-uptake in liver cells. Further evidence also show that GPER1 can downregulate Proprotein Convertase Subtilisin/ Kexin type 9, leading to suppression of LDL receptor breakdown. Here, we review how selective activation of GPER1 might prevent or suppress atherosclerosis, with less side effects than those of the non-selective estrogen.

[1]
Centers for Disease Control and Prevention (CDC) Million hearts: strategies to reduce the prevalence of leading cardiovascular disease risk factors--United States, 2011. MMWR Morb Mortal Wkly Rep, 2011, 60(36), 1248-1251.
[2]
Frostegård, J. Immunity, atherosclerosis and cardiovascular disease. BMC Med., 2013, 11(1), 117.
[http://dx.doi.org/10.1186/1741-7015-11-117] [PMID: 23635324]
[3]
Baradaran, A.J.J.o.n. Lipoprotein (a), type 2 diabetes and nephropathy; the mystery continues. J. Nephropathol., 2012, 1(3), 126.
[http://dx.doi.org/10.5812/nephropathol.8107]
[4]
Grebe, A.; Latz, E. Cholesterol crystals and inflammation. Curr. Rheumatol. Rep., 2013, 15(3), 313.
[http://dx.doi.org/10.1007/s11926-012-0313-z] [PMID: 23412688]
[5]
Tavafi, M.J.J.o.r.i.p. Complexity of diabetic nephropathy pathogenesis and design of investigations. J. Renal Inj. Prev., 2013, 2(2), 59-62.
[http://dx.doi.org/10.12861/jrip.2013.20]
[6]
Douglas, G.; Channon, K.M. The pathogenesis of atherosclerosis. Medicine, 2014, 42(9), 480-484.
[http://dx.doi.org/10.1016/j.mpmed.2014.06.011]
[7]
Virmani, R.; Burke, A.P.; Farb, A.; Kolodgie, F.D.J.J.o.t.A.C.o.C. Pathology of the vulnerable plaque. J. Am. Coll Cardiol., 2006, 47(8S), C13-C18.
[http://dx.doi.org/10.1002/9780470987575.ch2]
[8]
Lusis, A.J. Atherosclerosis. Nature, 2000, 407(6801), 233-241.
[http://dx.doi.org/10.1038/35025203] [PMID: 11001066]
[9]
Badimon, L.; Vilahur, G. Thrombosis formation on atherosclerotic lesions and plaque rupture. J. Intern. Med., 2014, 276(6), 618-632.
[http://dx.doi.org/10.1111/joim.12296] [PMID: 25156650]
[10]
Yu, X.H.; Fu, Y.C.; Zhang, D.W.; Yin, K.; Tang, C.K. Foam cells in atherosclerosis. Clin. Chim. Acta, 2013, 424, 245-252.
[http://dx.doi.org/10.1016/j.cca.2013.06.006] [PMID: 23782937]
[11]
Grover, S.P.; Mackman, N. Tissue factor in atherosclerosis and atherothrombosis. Atherosclerosis, 2020, 307, 80-86.
[http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.003] [PMID: 32674807]
[12]
Wilcox, J.N.; Smith, K.M.; Schwartz, S.M.; Gordon, D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. USA, 1989, 86(8), 2839-2843.
[http://dx.doi.org/10.1073/pnas.86.8.2839] [PMID: 2704749]
[13]
Cimmino, G.; D’Amico, C.; Vaccaro, V.; D’Anna, M.; Golino, P. The missing link between atherosclerosis, inflammation and thrombosis: Is it tissue factor? Expert Rev. Cardiovasc. Ther., 2011, 9(4), 517-523.
[http://dx.doi.org/10.1586/erc.11.40] [PMID: 21517734]
[14]
Toschi, V.; Gallo, R.; Lettino, M.; Fallon, J.T.; Gertz, S.D.; Ferna´ndez-Ortiz, A.; Chesebro, J.H.; Badimon, L.; Nemerson, Y.; Fuster, V.; Badimon, J.J. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation, 1997, 95(3), 594-599.
[http://dx.doi.org/10.1161/01.CIR.95.3.594] [PMID: 9024145]
[15]
Hoylaerts, M.; Rijken, D.C.; Lijnen, H.R.; Collen, D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J. Biol. Chem., 1982, 257(6), 2912-2919.
[http://dx.doi.org/10.1016/S0021-9258(19)81051-7] [PMID: 7199524]
[16]
Roger, V.L.; Go, A.S.; Lloyd-Jones, D.M.; Adams, R.J.; Berry, J.D.; Brown, T.M.; Carnethon, M.R.; Dai, S.; de Simone, G.; Ford, E.S.; Fox, C.S.; Fullerton, H.J.; Gillespie, C.; Greenlund, K.J.; Hailpern, S.M.; Heit, J.A.; Ho, P.M.; Howard, V.J.; Kissela, B.M.; Kittner, S.J.; Lackland, D.T.; Lichtman, J.H.; Lisabeth, L.D.; Makuc, D.M.; Marcus, G.M.; Marelli, A.; Matchar, D.B.; McDermott, M.M.; Meigs, J.B.; Moy, C.S.; Mozaffarian, D.; Mussolino, M.E.; Nichol, G.; Paynter, N.P.; Rosamond, W.D.; Sorlie, P.D.; Stafford, R.S.; Turan, T.N.; Turner, M.B.; Wong, N.D.; Wylie-Rosett, J. Heart disease and stroke statistics--2011 update: A report from the American Heart Association. Circulation, 2011, 123(4), e18-e209.
[http://dx.doi.org/10.1161/CIR.0b013e3182009701] [PMID: 21160056]
[17]
Shih, H.; Lee, B.; Lee, R.J.; Boyle, A.J. The aging heart and post-infarction left ventricular remodeling. J. Am. Coll. Cardiol., 2011, 57(1), 9-17.
[http://dx.doi.org/10.1016/j.jacc.2010.08.623] [PMID: 21185495]
[18]
Regitz-Zagrosek, V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat. Rev. Drug Discov., 2006, 5(5), 425-439.
[http://dx.doi.org/10.1038/nrd2032] [PMID: 16672926]
[19]
Hodis, H.N.; Mack, W.J. Hormone replacement therapy and the association with coronary heart disease and overall mortality: Clinical application of the timing hypothesis. J. Steroid Biochem. Mol. Biol., 2014, 142, 68-75.
[http://dx.doi.org/10.1016/j.jsbmb.2013.06.011] [PMID: 23851166]
[20]
Choi, Y.; Chang, Y.; Kim, B.K.; Kang, D.; Kwon, M.J.; Kim, C.W.; Jeong, C.; Ahn, Y.; Park, H.Y.; Ryu, S.; Cho, J. Menopausal stages and serum lipid and lipoprotein abnormalities in middle-aged women. Maturitas, 2015, 80(4), 399-405.
[http://dx.doi.org/10.1016/j.maturitas.2014.12.016] [PMID: 25631350]
[21]
Atsma, F.; Bartelink, M.L.E.L.; Grobbee, D.E.; van der Schouw, Y.T. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: A meta-analysis. Menopause, 2006, 13(2), 265-279.
[http://dx.doi.org/10.1097/01.gme.0000218683.97338.ea] [PMID: 16645540]
[22]
Turgeon, J.L.; McDonnell, D.P.; Martin, K.A.; Wise, P.M. Hormone therapy: Physiological complexity belies therapeutic simplicity. Science, 2004, 304(5675), 1269-1273.
[http://dx.doi.org/10.1126/science.1096725] [PMID: 15166356]
[23]
Fardoun, M.M.; Issa, K.; Maaliki, D.; Nasser, S.A.; Baydoun, E.; Eid, A.H. Estrogen increases expression of vascular alpha 2C adrenoceptor through the cAMP/Epac/JNK/AP-1 pathway and potentiates cold-induced vasoconstriction. Vascul. Pharmacol., 2020, 131, 106690.
[http://dx.doi.org/10.1016/j.vph.2020.106690] [PMID: 32407896]
[24]
Wehbe, Z.; Nasser, S.A.; El-Yazbi, A.; Nasreddine, S.; Eid, A.H. Estrogen and bisphenol A in hypertension. Curr. Hypertens. Rep., 2020, 22(3), 23.
[http://dx.doi.org/10.1007/s11906-020-1022-z] [PMID: 32114652]
[25]
Eid, A.H.; Maiti, K.; Mitra, S.; Chotani, M.A.; Flavahan, S.; Bailey, S.R.; Thompson-Torgerson, C.S.; Flavahan, N.A. Estrogen increases smooth muscle expression of α 2C -adrenoceptors and cold-induced constriction of cutaneous arteries. Am. J. Physiol. Heart Circ. Physiol., 2007, 293(3), H1955-H1961.
[http://dx.doi.org/10.1152/ajpheart.00306.2007] [PMID: 17644575]
[26]
Thomas, P.; Pang, Y.; Filardo, E.J.; Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 2005, 146(2), 624-632.
[http://dx.doi.org/10.1210/en.2004-1064] [PMID: 15539556]
[27]
Fardoun, M.; Dehaini, H.; Shaito, A.; Mesmar, J.; El-Yazbi, A.; Badran, A.; Beydoun, E.; Eid, A.H. The hypertensive potential of estrogen: An untold story. Vascul. Pharmacol., 2020, 124, 106600.
[http://dx.doi.org/10.1016/j.vph.2019.106600] [PMID: 31629918]
[28]
Dehaini, H.; Fardoun, M.; Abou-Saleh, H.; El-Yazbi, A.; Eid, A.A.; Eid, A.H. Estrogen in vascular smooth muscle cells: A friend or a foe? Vascul. Pharmacol., 2018, 111, 15-21.
[http://dx.doi.org/10.1016/j.vph.2018.09.001] [PMID: 30227233]
[29]
Hutchens, M.P.; Nakano, T.; Kosaka, Y.; Dunlap, J.; Zhang, W.; Herson, P.S.; Murphy, S.J.; Anderson, S.; Hurn, P.D. Estrogen is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo. Anesthesiology, 2010, 112(2), 395-405.
[http://dx.doi.org/10.1097/ALN.0b013e3181c98da9] [PMID: 20068453]
[30]
Chakrabarti, S.; Morton, J.S.; Davidge, S.T. Mechanisms of estrogen effects on the endothelium: An overview. Can. J. Cardiol., 2014, 30(7), 705-712.
[http://dx.doi.org/10.1016/j.cjca.2013.08.006] [PMID: 24252499]
[31]
Takada, Y.; Kato, C.; Kondo, S.; Korenaga, R.; Ando, J. Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem. Biophys. Res. Commun., 1997, 240(3), 737-741.
[http://dx.doi.org/10.1006/bbrc.1997.7734] [PMID: 9398636]
[32]
Filardo, E.J.; Quinn, J.A.; Bland, K.I.; Frackelton, A.R., Jr Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol., 2000, 14(10), 1649-1660.
[http://dx.doi.org/10.1210/mend.14.10.0532] [PMID: 11043579]
[33]
Zimmerman, M.A.; Budish, R.A.; Kashyap, S.; Lindsey, S.H. GPER–novel membrane oestrogen receptor. Clin. Sci., 2016, 130(12), 1005-1016.
[http://dx.doi.org/10.1042/CS20160114]
[34]
Meyer, M.R.; Amann, K.; Field, A.S.; Hu, C.; Hathaway, H.J.; Kanagy, N.L.; Walker, M.K.; Barton, M.; Prossnitz, E.R. Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction. Hypertension, 2012, 59(2), 507-512.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.184606] [PMID: 22203741]
[35]
Prabhushankar, R.; Krueger, C.; Manrique, C. Membrane estrogen receptors: Their role in blood pressure regulation and cardiovascular disease. Curr. Hypertens. Rep., 2014, 16(1), 408.
[http://dx.doi.org/10.1007/s11906-013-0408-6] [PMID: 24343167]
[36]
Barton, M.; Prossnitz, E.R. Emerging roles of GPER in diabetes and atherosclerosis. Trends Endocrinol. Metab., 2015, 26(4), 185-192.
[http://dx.doi.org/10.1016/j.tem.2015.02.003] [PMID: 25767029]
[37]
Burke, A.P.; Farb, A.; Malcom, G.; Virmani, R. Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis. Am. Heart J., 2001, 141(S2), S58-S62.
[http://dx.doi.org/10.1067/mhj.2001.109946] [PMID: 11174360]
[38]
Sever, R.; Glass, C.K. Signaling by nuclear receptors. Cold Spring Harb. Perspect. Biol., 2013, 5(3), a016709.
[http://dx.doi.org/10.1101/cshperspect.a016709] [PMID: 23457262]
[39]
Klinge, C.M.; Blankenship, K.A.; Risinger, K.E.; Bhatnagar, S.; Noisin, E.L.; Sumanasekera, W.K.; Zhao, L.; Brey, D.M.; Keynton, R.S. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J. Biol. Chem., 2005, 280(9), 7460-7468.
[http://dx.doi.org/10.1074/jbc.M411565200] [PMID: 15615701]
[40]
Cunningham, K.S.; Gotlieb, A.I. The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest., 2005, 85(1), 9-23.
[http://dx.doi.org/10.1038/labinvest.3700215] [PMID: 15568038]
[41]
Kaplan, J.R.; Manuck, S.B. Premenopausal reproductive health modulates future cardiovascular risk - comparative evidence from monkeys and women. Yale J. Biol. Med., 2017, 90(3), 499-507.
[PMID: 28955188]
[42]
Fairweather, D. Sex differences in inflammation during atherosclerosis. Clin. Med. Insights Cardiol., 2015, 8(S3), 49-59.
[PMID: 25983559]
[43]
Saha, K.R.; Rahman, M.M.; Paul, A.R.; Das, S.; Haque, S.; Jafrin, W.; Mia, A.R. Changes in lipid profile of postmenopausal women. Mymensingh Med. J., 2013, 22(4), 706-711.
[PMID: 24292300]
[44]
Vaisar, T.; Gordon, J.L.; Wimberger, J.; Heinecke, J.W.; Hinderliter, A.L.; Rubinow, D.R.; Girdler, S.S.; Rubinow, K.B. Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors. J. Clin. Lipidol., 2021, 15(1), 151-161.e0.
[http://dx.doi.org/10.1016/j.jacl.2020.11.009] [PMID: 33288437]
[45]
Lee, J.Y.; Hyun, H.S.; Park, H.G.; Seo, J.H.; Lee, E.Y.; Lee, J.S.; Lee, D.Y.; Choi, D.S.; Yoon, B.K. Effects of hormone therapy on serum lipid levels in postmenopausal korean women. J. Menopausal Med., 2015, 21(2), 104-111.
[http://dx.doi.org/10.6118/jmm.2015.21.2.104] [PMID: 26357648]
[46]
Borén, J.; Chapman, M.J.; Krauss, R.M.; Packard, C.J.; Bentzon, J.F.; Binder, C.J.; Daemen, M.J.; Demer, L.L.; Hegele, R.A.; Nicholls, S.J.; Nordestgaard, B.G.; Watts, G.F.; Bruckert, E.; Fazio, S.; Ference, B.A.; Graham, I.; Horton, J.D.; Landmesser, U.; Laufs, U.; Masana, L.; Pasterkamp, G.; Raal, F.J.; Ray, K.K.; Schunkert, H.; Taskinen, M.R.; van de Sluis, B.; Wiklund, O.; Tokgozoglu, L.; Catapano, A.L.; Ginsberg, H.N. Low-density lipoproteins cause atherosclerotic cardiovascular disease: Pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J., 2020, 41(24), 2313-2330.
[http://dx.doi.org/10.1093/eurheartj/ehz962] [PMID: 32052833]
[47]
Langer, G.; Bader, B.; Meoli, L.; Isensee, J.; Delbeck, M.; Noppinger, P.R.; Otto, C.J.S. A critical review of fundamental controversies in the field of GPR30 research. Steroids., 2010, 75(8-9), 603-610.
[http://dx.doi.org/10.1016/j.steroids.2009.12.006]
[48]
Meyer, M.R.; Fredette, N.C.; Howard, T.A.; Hu, C.; Ramesh, C.; Daniel, C.; Amann, K.; Arterburn, J.B.; Barton, M.; Prossnitz, E.R. G protein-coupled estrogen receptor protects from atherosclerosis. Sci. Rep., 2014, 4(1), 7564.
[http://dx.doi.org/10.1038/srep07564] [PMID: 25532911]
[49]
Hussain, Y.; Ding, Q.; Connelly, P.W.; Brunt, J.H.; Ban, M.R.; McIntyre, A.D.; Huff, M.W.; Gros, R.; Hegele, R.A.; Feldman, R.D. G-protein estrogen receptor as a regulator of low-density lipoprotein cholesterol metabolism: Cellular and population genetic studies. Arterioscler. Thromb. Vasc. Biol., 2015, 35(1), 213-221.
[http://dx.doi.org/10.1161/ATVBAHA.114.304326] [PMID: 25395619]
[50]
Fu, W.; Gao, X.P.; Zhang, S.; Dai, Y.P.; Zou, W.J.; Yue, L.M. 17β-estradiol inhibits pcsk9-mediated LDLR degradation through GPER/PLC activation in HepG2 Cells. Front. Endocrinol., 2020, 10, 930-930.
[http://dx.doi.org/10.3389/fendo.2019.00930] [PMID: 32082252]
[51]
Ding, Q.; Gros, R.; Limbird, L.E.; Chorazyczewski, J.; Feldman, R.D.J.A.J.o.P.-C.P. Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR 30. Am. J. Physiol. Cell Physiol., 2009, 297(5), C1178-C1187.
[http://dx.doi.org/10.1152/ajpcell.00185.2009] [PMID: 19741198]
[52]
Gros, R.; Hussain, Y.; Chorazyczewski, J.; Pickering, J.G.; Ding, Q.; Feldman, R.D.J.H. Extent of vascular remodeling is dependent on the balance between estrogen receptor α and G-protein–coupled estrogen receptor. Hypertension., 2016, 68(5), 1225-1235.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07859]
[53]
Sharma, G.; Prossnitz, E.R. Targeting the G protein-coupled estrogen receptor (GPER) in obesity and diabetes. Endo. Metab. Sci., 2021, 2, 100080.
[http://dx.doi.org/10.1016/j.endmts.2021.100080] [PMID: 35321004]
[54]
Haas, E.; Bhattacharya, I.; Brailoiu, E.; Damjanović, M.; Brailoiu, G.C.; Gao, X.; Mueller-Guerre, L.; Marjon, N.A.; Gut, A.; Minotti, R.; Meyer, M.R.; Amann, K.; Ammann, E.; Perez-Dominguez, A.; Genoni, M.; Clegg, D.J.; Dun, N.J.; Resta, T.C.; Prossnitz, E.R.; Barton, M. Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity. Circ. Res., 2009, 104(3), 288-291.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.190892] [PMID: 19179659]
[55]
Sharma, G.; Hu, C.; Brigman, J.L.; Zhu, G.; Hathaway, H.J.; Prossnitz, E.R. GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state. Endocrinology, 2013, 154(11), 4136-4145.
[http://dx.doi.org/10.1210/en.2013-1357] [PMID: 23970785]
[56]
Davis, K.E.; Carstens, E.J.; Irani, B.G.; Gent, L.M.; Hahner, L.M.; Clegg, D.J. Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm. Behav., 2014, 66(1), 196-207.
[http://dx.doi.org/10.1016/j.yhbeh.2014.02.004] [PMID: 24560890]
[57]
Sharma, G.; Hu, C.; Staquicini, D.I.; Brigman, J.L.; Liu, M.; Mauvais-Jarvis, F.; Pasqualini, R.; Arap, W.; Arterburn, J.B.; Hathaway, H.J.; Prossnitz, E.R. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci. Transl. Med., 2020, 12(528), eaau5956.
[http://dx.doi.org/10.1126/scitranslmed.aau5956] [PMID: 31996464]
[58]
Mårtensson, U.E.A.; Salehi, S.A.; Windahl, S.; Gomez, M.F.; Swärd, K.; Daszkiewicz-Nilsson, J.; Wendt, A.; Andersson, N.; Hellstrand, P.; Grände, P.O.; Owman, C.; Rosen, C.J.; Adamo, M.L.; Lundquist, I.; Rorsman, P.; Nilsson, B.O.; Ohlsson, C.; Olde, B.; Leeb-Lundberg, L.M.F. Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology, 2009, 150(2), 687-698.
[http://dx.doi.org/10.1210/en.2008-0623] [PMID: 18845638]
[59]
Muller, C.; Brown-Glaberman, U.A.; Chaney, M.F.; Garyantes, T.; LoRusso, P.; McQuade, J.L.; Mita, A.C.; Mita, M.M.; Natale, C.; Orloff, M.; Papadopoulos, K.P.; Sato, T.; Yilmaz, E.; Rodon, J. Phase 1 trial of a novel, first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in patients with advanced or recurrent treatment-refractory solid malignancies. J. Clin. Oncol., 2021, 39(S15), 3084-3084.
[http://dx.doi.org/10.1200/JCO.2021.39.15_suppl.3084]
[60]
Beyoğlu, A.; Kurutaş, E.B.; Karaküçük, Y.; Çömez, A.; Meşen, A. Comparing the effects of serum GPER-1 and oxidant/antioxidant levels on retinopathy in patients with diabetes and healthy individuals: a pilot study. Arq. Bras. Oftalmol., 2022, S0004-27492022005008205.
[PMID: 35857982]
[61]
Kastenberger, I.; Lutsch, C.; Schwarzer, C. Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol. Psychopharmacology, 2012, 221(3), 527-535.
[http://dx.doi.org/10.1007/s00213-011-2599-3] [PMID: 22143579]
[62]
Sarma, S.; Sockalingam, S.; Dash, S. Obesity as a MULTISYSTEM disease: Trends in obesity rates and OBESITY‐RELATED complications. Diabetes Obes. Metab., 2021, 23(S1), 3-16.
[http://dx.doi.org/10.1111/dom.14290] [PMID: 33621415]
[63]
Sandesara, P.B.; Virani, S.S.; Fazio, S.; Shapiro, M.D. The forgotten lipids: Triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr. Rev., 2019, 40(2), 537-557.
[http://dx.doi.org/10.1210/er.2018-00184] [PMID: 30312399]
[64]
Huang, D.; Wang, X.; Zhu, Y.; Gong, J.; Liang, J.; Song, Y.; Zhang, Y.; Liu, L.; Wei, C. Bazi bushen capsule alleviates post-menopausal atherosclerosis via gper1-dependent anti-inflammatory and anti-apoptotic effects. Front. Pharmacol., 2021, 12, 658998.
[http://dx.doi.org/10.3389/fphar.2021.658998] [PMID: 34248622]
[65]
Beral, V.; Bull, D.; Reeves, G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet, 2005, 365(9470), 1543-1551.
[http://dx.doi.org/10.1016/S0140-6736(05)66455-0] [PMID: 15866308]
[66]
Furness, S.; Roberts, H.; Marjoribanks, J.; Lethaby, A. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst. Rev., 2012, 2012(8), CD000402.
[http://dx.doi.org/10.1002/14651858.CD000402.pub4]
[67]
Wildemeersch, D. Why perimenopausal women should consider to use a levonorgestrel intrauterine system. Gynecol. Endocrinol., 2016, 32(8), 659-661.
[http://dx.doi.org/10.3109/09513590.2016.1153056] [PMID: 26930021]
[68]
Pinkerton, J.V.; Pickar, J.H.; Racketa, J.; Mirkin, S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric, 2012, 15(5), 411-418.
[http://dx.doi.org/10.3109/13697137.2012.696289] [PMID: 22853444]
[69]
Singh, G.; Puckett, Y. Endometrial Hyperplasia. In StatPearls; StatPearls Publishing Copyright© 2022; StatPearls Publishing LLC: Treasure Island, FL, 2022.
[70]
Hamoda, H.; Panay, N.; Pedder, H.; Arya, R.; Savvas, M. The british menopause society & women’s health concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod. Health, 2020, 26(4), 181-209.
[http://dx.doi.org/10.1177/2053369120957514] [PMID: 33045914]
[71]
Gompel, A. Progesterone and endometrial cancer. Best Pract. Res. Clin. Obstet. Gynaecol., 2020, 69, 95-107.
[http://dx.doi.org/10.1016/j.bpobgyn.2020.05.003] [PMID: 32732107]
[72]
De Medeiros, S.F.; Yamamoto, M.M.W.; Barbosa, J.S. Abnormal bleeding during menopause hormone therapy: insights for clinical management. Clin. Med. Insights Womens Health, 2013, 6, CMWH.S10483.
[http://dx.doi.org/10.4137/CMWH.S10483] [PMID: 24665210]
[73]
Edwards, M.; Can, A.S. In StatPearls; StatPearls Publishing Copyright© 2022; StatPearls Publishing LLC: Treasure Island, FL, 2022.
[74]
Mu, E.; Kulkarni, J. Hormonal contraception and mood disorders. Aust. Prescr., 2022, 45(3), 75-79.
[http://dx.doi.org/10.18773/austprescr.2022.025] [PMID: 35755988]
[75]
Dennis, M.K.; Burai, R.; Ramesh, C.; Petrie, W.K.; Alcon, S.N.; Nayak, T.K.; Bologa, C.G.; Leitao, A.; Brailoiu, E.; Deliu, E.; Dun, N.J.; Sklar, L.A.; Hathaway, H.J.; Arterburn, J.B.; Oprea, T.I.; Prossnitz, E.R. In vivo effects of a GPR30 antagonist. Nat. Chem. Biol., 2009, 5(6), 421-427.
[http://dx.doi.org/10.1038/nchembio.168] [PMID: 19430488]
[76]
Barton, M. Position paper: The membrane estrogen receptor GPER – Clues and questions. Steroids, 2012, 77(10), 935-942.
[http://dx.doi.org/10.1016/j.steroids.2012.04.001] [PMID: 22521564]
[77]
DeLeon, C.; Wang, D.Q.H.; Arnatt, C.K. G protein-coupled estrogen receptor, GPER1, offers a novel target for the treatment of digestive diseases. Front. Endocrinol., 2020, 11, 578536.
[http://dx.doi.org/10.3389/fendo.2020.578536] [PMID: 33281743]
[78]
Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol., 2019, 116, 135-170.
[http://dx.doi.org/10.1016/bs.apcsb.2019.01.001] [PMID: 31036290]
[79]
Rodriguez, A.C.; Blanchard, Z.; Maurer, K.A.; Gertz, J. Estrogen signaling in endometrial cancer: A key oncogenic pathway with several open questions. Horm. Cancer, 2019, 10(2-3), 51-63.
[http://dx.doi.org/10.1007/s12672-019-0358-9] [PMID: 30712080]
[80]
Krakstad, C.; Trovik, J.; Wik, E.; Engelsen, I.B.; Werner, H.M.J.; Birkeland, E.; Raeder, M.B.; Øyan, A.M.; Stefansson, I.M.; Kalland, K.H.; Akslen, L.A.; Salvesen, H.B. Loss of GPER identifies new targets for therapy among a subgroup of ERα-positive endometrial cancer patients with poor outcome. Br. J. Cancer, 2012, 106(10), 1682-1688.
[http://dx.doi.org/10.1038/bjc.2012.91] [PMID: 22415229]
[81]
Skrzypczak, M.; Schüler, S.; Lattrich, C.; Ignatov, A.; Ortmann, O.; Treeck, O. G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines. Steroids, 2013, 78(11), 1087-1091.
[http://dx.doi.org/10.1016/j.steroids.2013.07.007] [PMID: 23921077]
[82]
Levine, D.A.; Schultz, N.; Cherniack, A.D.; Akbani, R.; Liu, Y.; Shen, H.; Robertson, A.G.; Pashtan, I.; Shen, R.; Benz, C.C.; Yau, C.; Laird, P.W.; Ding, L.; Zhang, W.; Mills, G.B.; Kucherlapati, R.; Mardis, E.R.; Levine, D.A. Integrated genomic characterization of endometrial carcinoma. Nature, 2013, 497(7447), 67-73.
[http://dx.doi.org/10.1038/nature12113] [PMID: 23636398]
[83]
Kim, K.H.; Bender, J.R. Rapid, estrogen receptor-mediated signaling: Why is the endothelium so special? Sci. STKE, 2005, 2005(288), pe28.
[http://dx.doi.org/10.1126/stke.2882005pe28] [PMID: 15956360]
[84]
Otto, C.; Fuchs, I.; Kauselmann, G.; Kern, H.; Zevnik, B.; Andreasen, P.; Schwarz, G.; Altmann, H.; Klewer, M.; Schoor, M.; Vonk, R.; Fritzemeier, K.H. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol. Reprod., 2009, 80(1), 34-41.
[http://dx.doi.org/10.1095/biolreprod.108.071175] [PMID: 18799753]
[85]
Isensee, J.; Meoli, L.; Zazzu, V.; Nabzdyk, C.; Witt, H.; Soewarto, D.; Effertz, K.; Fuchs, H.; Gailus-Durner, V.; Busch, D.; Adler, T.; de Angelis, M.H.; Irgang, M.; Otto, C.; Noppinger, P.R. Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology, 2009, 150(4), 1722-1730.
[http://dx.doi.org/10.1210/en.2008-1488] [PMID: 19095739]
[86]
Fardoun, M.; Mondello, S.; Kobeissy, F.; Eid, A.H. G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon. Front. Pharmacol., 2022, 13, 1061374.
[http://dx.doi.org/10.3389/fphar.2022.1061374] [PMID: 36438809]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version366msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[08:57:38] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[08:57:38] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[08:57:38] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[08:57:38] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[08:57:38] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (133ms)time
  • Application (232ms)time
  • 1 x Application (63.54%)
    232ms
    1 x Booting (36.46%)
    133ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated159ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('221975217','',1,1740473858,1740473858) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740473858
      970μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('221975217','/article/131361',1,1740473858,1740473858)
      200μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 221975217 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221975217) limit 1
      25.5msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 221975217
      • 1: 221975217
      • 2: 221975217
      • 3: 221975217
      • 4: 221975217
      • 5: 221975217
      • 6: 221975217
      • 7: 221975217
      • 8: 221975217
      • 9: 221975217
      • 10: 221975217
      • 11: 221975217
      • 12: 221975217
      • 13: 221975217
      • 14: 221975217
      • 15: 221975217
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=131361
      730μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      820μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      1.36msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.16msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.36msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.75msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '131361'
      220μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 131361
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '131361'
      4.98msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 131361
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '131361' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.16msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 131361
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      260μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      560μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      33.24msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      30.63msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      25.13msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 131361 limit 1
      230μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 131361
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 131361 and content_type = 'article' order by status desc limit 1
      250μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 216400 limit 1
      210μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 216400
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      230μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      350μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '131361' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      370μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '13411' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      310μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '3436' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      280μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436)
      15.41msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411)
      620μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 131361) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 131361) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 221975217 and j.to_ip >=221975217 )) and ((j.from_date <= 1740473858 and j.to_date >= 1740473858 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 131361)
      550μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '4312' and is_uploaded = 1 and issue_id = 13411 order by cast(first_page as SIGNED) desc limit 1
      500μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 4312
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '4319' and is_uploaded = 1 and issue_id = 13411 order by cast(first_page as SIGNED) asc limit 1
      420μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 4319
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      180μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      160μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 131361 limit 1
      2.23msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 131361
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740473858 and `b`.`banner_to_date` >= 1740473858 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.1msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740473858
      • 4: 1740473858
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740473858 and `b`.`banner_to_date` >= 1740473858 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.45msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740473858
      • 4: 1740473858
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='b3a310a6d104bca2588e72220380d4c4'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        XokMBFeHmhQQtYpow2PH2nISp7fRPVZqoZESqqFL
        uc_cart_id
        b3a310a6d104bca2588e72220380d4c4
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/131361" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/131361
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 08:57:38 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkxkVkV5eGlrRTNiaUoyT3BsTXo4Y0E9PSIsInZhbHVlIjoiRksvNWV4ZEdYZThNRkt5eCtwL0plL01nODZqenkvQ3N6RzN0dUFXOG53MnFzWGlXekVkWjFsNUk3VlZhT1haNlZPZVRQd0c5NURiQlVBQkErZ1BLaVpLOVpnclJ0M1JERlRKdFZFZk1kUU10RnMwajd2aXNRRWJvYVJxdDFsdGoiLCJtYWMiOiI0ZDZhNTI0ZDE3YTM0MWUwNWM4YzI0NDlmMGVjMjI4MmI4NGJkZWFiN2QyNTY3M2Q4NzczYzAxYjIwMGYyYzI2IiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 20:57:38 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkxkVkV5eGlrRTNiaUoyT3BsTXo4Y0E9PSIsInZhbHVlIjoiRksvNWV4ZEdYZThNRkt5eCtwL0plL01nODZqenkvQ3N6RzN0dUFXOG53MnFzWGlXekVkWjFsNUk3VlZhT1haNlZPZVRQd" 1 => "alphaeurekaselectnet_session=eyJpdiI6InRDOVlhOEdLaGsydVJYQlc0MFpMeFE9PSIsInZhbHVlIjoiU0Vwa3lQZGpzL0w5L0JONVlsQ3pZRkNSTi9pNkwyVGVrNHlBaFZmMks2UFdmUTd2VTJTRURxUjluRS9hQSs0MlJHN1NLTGxSWnl5Q09qbm5WeVdxL2ZHckxJWUxnNlJOS2hUdXowVEhmMTNFUVNSanpiaXJCTWw0U1JGdUNXd2ciLCJtYWMiOiI2OTJkYjgxMjZhOTRjZDQ4YjM1MzAzODQ0ZjJmMjhiMmIxMmM3M2EzMTFhNTgzNzc3YWZjYTI3ODQyYWQ4NmE1IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InRDOVlhOEdLaGsydVJYQlc0MFpMeFE9PSIsInZhbHVlIjoiU0Vwa3lQZGpzL0w5L0JONVlsQ3pZRkNSTi9pNkwyVGVrNHlBaFZmMks2UFdmUTd2VTJTRURxUjl" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkxkVkV5eGlrRTNiaUoyT3BsTXo4Y0E9PSIsInZhbHVlIjoiRksvNWV4ZEdYZThNRkt5eCtwL0plL01nODZqenkvQ3N6RzN0dUFXOG53MnFzWGlXekVkWjFsNUk3VlZhT1haNlZPZVRQd0c5NURiQlVBQkErZ1BLaVpLOVpnclJ0M1JERlRKdFZFZk1kUU10RnMwajd2aXNRRWJvYVJxdDFsdGoiLCJtYWMiOiI0ZDZhNTI0ZDE3YTM0MWUwNWM4YzI0NDlmMGVjMjI4MmI4NGJkZWFiN2QyNTY3M2Q4NzczYzAxYjIwMGYyYzI2IiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 20:57:38 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkxkVkV5eGlrRTNiaUoyT3BsTXo4Y0E9PSIsInZhbHVlIjoiRksvNWV4ZEdYZThNRkt5eCtwL0plL01nODZqenkvQ3N6RzN0dUFXOG53MnFzWGlXekVkWjFsNUk3VlZhT1haNlZPZVRQd" 1 => "alphaeurekaselectnet_session=eyJpdiI6InRDOVlhOEdLaGsydVJYQlc0MFpMeFE9PSIsInZhbHVlIjoiU0Vwa3lQZGpzL0w5L0JONVlsQ3pZRkNSTi9pNkwyVGVrNHlBaFZmMks2UFdmUTd2VTJTRURxUjluRS9hQSs0MlJHN1NLTGxSWnl5Q09qbm5WeVdxL2ZHckxJWUxnNlJOS2hUdXowVEhmMTNFUVNSanpiaXJCTWw0U1JGdUNXd2ciLCJtYWMiOiI2OTJkYjgxMjZhOTRjZDQ4YjM1MzAzODQ0ZjJmMjhiMmIxMmM3M2EzMTFhNTgzNzc3YWZjYTI3ODQyYWQ4NmE1IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InRDOVlhOEdLaGsydVJYQlc0MFpMeFE9PSIsInZhbHVlIjoiU0Vwa3lQZGpzL0w5L0JONVlsQ3pZRkNSTi9pNkwyVGVrNHlBaFZmMks2UFdmUTd2VTJTRURxUjl" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "XokMBFeHmhQQtYpow2PH2nISp7fRPVZqoZESqqFL" "uc_cart_id" => "b3a310a6d104bca2588e72220380d4c4" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/131361" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 08:57:38GET/article/131361514361