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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Current Frontiers

Understanding the Phytoestrogen Genistein Actions on Breast Cancer: Insights on Estrogen Receptor Equivalence, Pleiotropic Essence and Emerging Paradigms in Bioavailability Modulation

Author(s): Parth Malik, Raj Singh, Mukesh Kumar, Anuj Malik and Tapan Kumar Mukherjee*

Volume 23, Issue 15, 2023

Published on: 02 February, 2023

Page: [1395 - 1413] Pages: 19

DOI: 10.2174/1568026623666230103163023

Price: $65

Abstract

Prevalent as a major phenolic ingredient of soy and soy products, genistein is recognized as an eminent phytoestrogen owing to its interacting ability with estrogen receptors (ERs). The metabolic conversion of plant-derived genistin to genistein by gut microbes and intestinal enzymes enhances its absorption at intestinal pH of ~7.5-7.8. Genistein interferes in breast cancer (BC) development via pleiotropic actions on cell proliferation, survival, angiogenesis, and apoptosis. Though multiple investigations have demonstrated genistein intake-driven reduced BC risk, similar efficacy has not been replicated in clinical trials. Furthermore, multiple studies have structurally and functionally equated genistein extents with 17-β-estradiol (E2), the most available physiological estrogen in females, culminating in aggravated BC growth. Of note, both genistein and E2 function via interacting with ERs (ERα and ERβ). However, although E2 shows almost equal affinity towards both ERα and ERβ, genistein shows more affinity towards ERβ than ERα. Our cautious literature survey revealed typical intake mode, ER expression pattern and the ratio of ERα and ERβ, transactivators/ regulators of ERα and ERβ expression and activities, patient age, and menopausal status as decisive factors affecting genistein BC activities. Of further interest are the mechanisms by which genistein inhibits triple-negative breast cancers (TNBCs), which lack ERs, progesterone receptors (PRs), and human epidermal growth factor receptors (HER2). Herein, we attempt to understand the dosage-specific genistein actions in BC cells and patients with an insight into its better response via derivative development, nanocarrier-assisted, and combinatorial delivery with chemotherapeutic drugs.

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[1]
Maitra, R.; Malik, P.; Mukherjee, T.K. Targeting estrogens and various estrogen-related receptors against non-small cell lung cancers: A perspective. Cancers (Basel), 2021, 14(1), 80.
[http://dx.doi.org/10.3390/cancers14010080] [PMID: 35008242]
[2]
Crisafulli, A.; Marini, H.; Bitto, A.; Altavilla, D.; Squadrito, G.; Romeo, A.; Adamo, E.B.; Marini, R.; D’Anna, R.; Corrado, F.; Bartolone, S.; Frisina, N.; Squadrito, F. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause, 2004, 11(4), 400-404.
[http://dx.doi.org/10.1097/01.GME.0000109314.11228.E5] [PMID: 15243277]
[3]
Trock, B.J.; Hilakivi-Clarke, L.; Clarke, R. Meta-analysis of soy intake and breast cancer risk. J. Natl. Cancer Inst., 2006, 98(7), 459-471.
[http://dx.doi.org/10.1093/jnci/djj102] [PMID: 16595782]
[4]
Cornwell, T.; Cohick, W.; Raskin, I. Dietary phytoestrogens and health. Phytochemistry, 2004, 65(8), 995-1016.
[http://dx.doi.org/10.1016/j.phytochem.2004.03.005] [PMID: 15110680]
[5]
Reinli, K.; Block, G. Phytoestrogen content of foods-a compendium of literature values. Nutr. Cancer, 1996, 26(2), 123-148.
[http://dx.doi.org/10.1080/01635589609514470] [PMID: 8875551]
[6]
Maggiolini, M.; Bonofiglio, D.; Marsico, S.; Panno, M.L.; Cenni, B.; Picard, D.; Andò, S. Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol. Pharmacol., 2001, 60(3), 595-602.
[PMID: 11502892]
[7]
Torrens-Mas, M.; Roca, P. Phytoestrogens for cancer prevention and treatment. Biology (Basel), 2020, 9(12), 427.
[http://dx.doi.org/10.3390/biology9120427] [PMID: 33261116]
[8]
Setchell, K.D.R.; Brown, N.M.; Zimmer-Nechemias, L.; Brashear, W.T.; Wolfe, B.E.; Kirschner, A.S.; Heubi, J.E. Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. Am. J. Clin. Nutr., 2002, 76(2), 447-453.
[http://dx.doi.org/10.1093/ajcn/76.2.447] [PMID: 12145021]
[9]
Chiou, Y.S.; Wu, J.C.; Huang, Q.; Shahidi, F.; Wang, Y.J.; Ho, C.T.; Pan, M.H. Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary polyphenols. J. Funct. Foods, 2014, 7, 3-25.
[http://dx.doi.org/10.1016/j.jff.2013.08.006]
[10]
Lavigne, J.A.; Takahashi, Y.; Chandramouli, G.V.R.; Liu, H.; Perkins, S.N.; Hursting, S.D.; Wang, T.T.Y. Concentration-dependent effects of genistein on global gene expression in MCF-7 breast cancer cells: an oligo microarray study. Breast Cancer Res. Treat., 2008, 110(1), 85-98.
[http://dx.doi.org/10.1007/s10549-007-9705-6] [PMID: 17687646]
[11]
Hsieh, C.Y.; Santell, R.C.; Haslam, S.Z.; Helferich, W.G. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res., 1998, 58(17), 3833-3838.
[PMID: 9731492]
[12]
Miodini, P.; Fioravanti, L.; Fronzo, G.D.; Cappelletti, V. The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br. J. Cancer, 1999, 80(8), 1150-1155.
[http://dx.doi.org/10.1038/sj.bjc.6690479] [PMID: 10376965]
[13]
Barkhem, T.; Carlsson, B.; Nilsson, Y.; Enmark, E.; Gustafsson, J.Å.; Nilsson, S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol., 1998, 54(1), 105-112.
[http://dx.doi.org/10.1124/mol.54.1.105] [PMID: 9658195]
[14]
Kuiper, G.G.J.M.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.Å. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology, 1998, 139(10), 4252-4263.
[http://dx.doi.org/10.1210/endo.139.10.6216] [PMID: 9751507]
[15]
Kuiper, G.G.J.M.; Carlsson, B.; Grandien, K.; Enmark, E.; Häggblad, J.; Nilsson, S.; Gustafsson, J.Å. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology, 1997, 138(3), 863-870.
[http://dx.doi.org/10.1210/endo.138.3.4979] [PMID: 9048584]
[16]
Mei, J.; Chen, X.; Liu, J.; Yi, Y.; Zhang, Y.; Ying, G. A biotransformation process for production of genistein from sophoricoside by a strain of Rhizopusoryza. Sci. Rep., 2019, 9(1), 6564.
[http://dx.doi.org/10.1038/s41598-019-42996-z] [PMID: 31024087]
[17]
Łuczkiewicz, M.; Głód, D. Callus cultures of Genista plants-in vitro material producing high amounts of isoflavones of phytoestrogenic activity. Plant Sci., 2003, 165(5), 1101-1108.
[http://dx.doi.org/10.1016/S0168-9452(03)00305-4]
[18]
Lucchesini, M.; Bertoli, A.; Mensuali-Sodi, A.; Cappelli, E.; Noccioli, C.; Luciardi, L.; Pistelli, L. Cytisusaeolicus Guss. Ex Lindl. in vitro cultures and genistin production. Cent. Eur. J. Biol., 2010, 5(1), 111-120.
[http://dx.doi.org/10.2478/s11535-009-0067-4]
[19]
Goyal, S.; Ramawat, K.G. Effect of chemical factors on production of isoflavonoids in Pueraria tuberosa (Roxb.ex.Willd.) DC suspension culture. Indian J. Exp. Biol., 2007, 45(12), 1063-1067.
[PMID: 18254213]
[20]
Rani, D.; Buranasudja, V.; Kobtrakul, K.; De-Eknamkul, W.; Vimolmangkang, S. Elicitation of Pueraria candollei var. mirifica suspension cells promises antioxidant potential, implying antiaging activity. Plant Cell Tissue Organ Cult., 2021, 145(1), 29-41.
[http://dx.doi.org/10.1007/s11240-020-01990-4]
[21]
Veitch, N.C. Isoflavonoids of the Leguminosae. Nat. Prod. Rep., 2013, 30(7), 988-1027.
[http://dx.doi.org/10.1039/c3np70024k] [PMID: 23736284]
[22]
Wang, X. Structural studies and mechanisms of isoflavonoid biosynthesis.In: Isoflavones, Biosynthesis Occurrence and Health Effects; Thompson, M.J., Ed.; Nova Science Publishers, 2010, pp. 239-254.
[23]
Xu, X.; Harris, K.S.; Wang, H.J.; Murphy, P.A.; Hendrich, S. Bioavailability of soybean isoflavones depends upon gut microflora in women. J. Nutr., 1995, 125(9), 2307-2315.
[http://dx.doi.org/10.1093/jn/125.9.2307] [PMID: 7666247]
[24]
Beekmann, K.; de Haan, L.H.J.; Actis-Goretta, L.; Houtman, R.; van Bladeren, P.J.; Rietjens, I.M.C.M. The effect of glucuronidation on isoflavone induced estrogen receptor (ER)α and ERβ; mediated coregulator interactions. J. Steroid Biochem. Mol. Biol., 2015, 154, 245-253.
[http://dx.doi.org/10.1016/j.jsbmb.2015.09.002] [PMID: 26361015]
[25]
Yuan, B.; Wang, L.; Jin, Y.; Zhen, H.; Xu, P.; Xu, Y.; Li, C.; Xu, H. Role of metabolism in the effects of genistein and its phase II conjugates on the growth of human breast cell lines. AAPS J., 2012, 14(2), 329-344.
[http://dx.doi.org/10.1208/s12248-012-9338-5] [PMID: 22415614]
[26]
Islam, M.A.; Bekele, R. vanden Berg, J.H.J.; Kuswanti, Y.; Thapa, O.; Soltani, S.; van Leeuwen, F.X.R.; Rietjens, I.M.C.M.; Murk, A.J. Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. Toxicol. In Vitro, 2015, 29(4), 706-715.
[http://dx.doi.org/10.1016/j.tiv.2015.01.013] [PMID: 25661160]
[27]
Kaneko, A.; Matsumoto, T.; Matsubara, Y.; Sekiguchi, K.; Koseki, J.; Yakabe, R.; Aoki, K.; Aiba, S.; Yamasaki, K. Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β;-glucuronidase in macrophages. Immun. Inflamm. Dis., 2017, 5(3), 265-279.
[http://dx.doi.org/10.1002/iid3.163] [PMID: 28480538]
[28]
Yuan, L.; Wagatsuma, C.; Yoshida, M.; Miura, T.; Mukoda, T.; Fujii, H.; Sun, B.; Kim, J.H.; Surh, Y.J. Inhibition of human breast cancer growth by GCP™ (genistein combined polysaccharide) in xenogeneic athymic mice: involvement of genistein biotransformation by β;-glucuronidase from tumor tissues. Mutat. Res., 2003, 523-524, 55-62.
[http://dx.doi.org/10.1016/S0027-5107(02)00321-4] [PMID: 12628503]
[29]
Peterkin, V.C.; Bauman, J.N.; Goosen, T.C.; Menning, L.; Man, M.Z.; Paulauskis, J.D.; Williams, J.A.; Myrand, S.P. Limited influence of UGT1A1*28 and no effect of UGT2B7*2 polymorphisms on UGT1A1 or UGT2B7 activities and protein expression in human liver microsomes. Br. J. Clin. Pharmacol., 2007, 64(4), 458-468.
[http://dx.doi.org/10.1111/j.1365-2125.2007.02923.x] [PMID: 17555467]
[30]
Nagar, S.; Walther, S.; Blanchard, R.L. Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol. Pharmacol., 2006, 69(6), 2084-2092.
[http://dx.doi.org/10.1124/mol.105.019240] [PMID: 16517757]
[31]
Liang, Y.; Zhao, W.; Wang, C.; Wang, Z.; Wang, Z.; Zhang, J. A comprehensive screening and identification of genistin metabolites in rats based on multiple metabolite templates combined with UHPLC-HRMS analysis. Molecules, 2018, 23(8), 1862.
[http://dx.doi.org/10.3390/molecules23081862] [PMID: 30049985]
[32]
Mukund, V.; Mukund, D.; Sharma, V.; Mannarapu, M.; Alam, A. Genistein: Its role in metabolic diseases and cancer. Crit. Rev. Oncol. Hematol., 2017, 119, 13-22.
[http://dx.doi.org/10.1016/j.critrevonc.2017.09.004] [PMID: 29065980]
[33]
Schoefer, L.; Mohan, R.; Braune, A.; Birringer, M.; Blaut, M. Anaerobic C-ring cleavage of genistein and daidzein by Eubacterium ramulus. FEMS Microbiol. Lett., 2002, 208(2), 197-202.
[http://dx.doi.org/10.1111/j.1574-6968.2002.tb11081.x] [PMID: 11959436]
[34]
Eckburg, P.B.; Bik, E.M.; Bernstein, C.N.; Purdom, E.; Dethlefsen, L.; Sargent, M.; Gill, S.R.; Nelson, K.E.; Relman, D.A. Diversity of the human intestinal microbial flora. Science, 2005, 308(5728), 1635-1638.
[http://dx.doi.org/10.1126/science.1110591] [PMID: 15831718]
[35]
Nan, G.; Shi, J.; Huang, Y.; Sun, J.; Lv, J.; Yang, G.; Li, Y. Dissociation constants and solubilities of Daidzein and Genistein in different solvents. J. Chem. Eng. Data, 2014, 59(4), 1304-1311.
[http://dx.doi.org/10.1021/je4010905]
[36]
Ungar, Y.; Osundahunsi, O.F.; Shimoni, E. Thermal stability of genistein and daidzein and its effect on their antioxidant activity. J. Agric. Food Chem., 2003, 51(15), 4394-4399.
[http://dx.doi.org/10.1021/jf034021z] [PMID: 12848516]
[37]
Malik, P.; Mukherjee, T.K. Structure-Function elucidation of antioxidative and prooxidative activities of the polyphenolic compound curcumin. Zhongguo Shengwuzhipinxue Zazhi, 2014, 2014, 1-8.
[http://dx.doi.org/10.1155/2014/396708]
[38]
Malik, P.; Inwati, G.K.; Mukherjee, T.K.; Singh, S.; Singh, M. Green silver nanoparticle and Tween-20 modulated pro-oxidant to antioxidant curcumin transformation in aqueous CTAB stabilized peanut oil emulsions. J. Mol. Liq., 2019, 291, 111252.
[http://dx.doi.org/10.1016/j.molliq.2019.111252]
[39]
Malik, P.; Hoidal, J.R.; Mukherjee, T.K. Recent advances in curcumin treated non-small cell lung cancers: an impetus of pleiotropic traits and nanocarrier aided delivery. Curr. Med. Chem., 2020, 27, 1-45.
[http://dx.doi.org/10.2174/0929867327666200824110332] [PMID: 32838707]
[40]
Ginsburg, E.S.; Gao, X.; Shea, B.F.; Barbieri, R.L. Half-life of estradiol in postmenopausal women. Gynecol. Obstet. Invest., 1998, 45(1), 45-48.
[http://dx.doi.org/10.1159/000009923] [PMID: 9473164]
[41]
Pike, A.C.W.; Brzozowski, A.M.; Hubbard, R.E.; Bonn, T.; Thorsell, A.G.; Engström, O.; Ljunggren, J.; Gustafsson, J.A.; Carlquist, M. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J., 1999, 18(17), 4608-4618.
[http://dx.doi.org/10.1093/emboj/18.17.4608] [PMID: 10469641]
[42]
Le Bail, J.C.; Champavier, Y.; Chulia, A.J.; Habrioux, G. Effects of phytoestrogens on aromatase, 3β; and 17β;-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci., 2000, 66(14), 1281-1291.
[http://dx.doi.org/10.1016/S0024-3205(00)00435-5] [PMID: 10755463]
[43]
Jiang, H.; Fan, J.; Cheng, L.; Hu, P.; Liu, R. The anticancer activity of genistein is increased in estrogen receptor beta 1-positive breast cancer cells. OncoTargets Ther., 2018, 11, 8153-8163.
[http://dx.doi.org/10.2147/OTT.S182239] [PMID: 30532556]
[44]
Mukherjee, T.K.; Nathan, L.; Dinh, H.; Reddy, S.T.; Chaudhuri, G. 17-epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting VCAM-1 mRNA expression. J. Biol. Chem., 2003, 278, 11746-11752.
[http://dx.doi.org/10.1074/jbc.M207800200] [PMID: 12547825]
[45]
Chang, E.C.; Charn, T.H.; Park, S.H.; Helferich, W.G.; Komm, B.; Katzenellenbogen, J.A.; Katzenellenbogen, B.S. Estrogen Receptors α and β; as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol. Endocrinol., 2008, 22(5), 1032-1043.
[http://dx.doi.org/10.1210/me.2007-0356] [PMID: 18258689]
[46]
Kumar, S.; Lata, K.; Mukhopadhyay, S.; Mukherjee, T.K. Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: A perspective. Biochim. Biophys. Acta, Gen. Subj., 2010, 1800(10), 1127-1135.
[http://dx.doi.org/10.1016/j.bbagen.2010.04.011] [PMID: 20434525]
[47]
Clark, G.M.; Osborne, C.K.; McGuire, W.L. Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J. Clin. Oncol., 1984, 2(10), 1102-1109.
[http://dx.doi.org/10.1200/JCO.1984.2.10.1102] [PMID: 6491696]
[48]
Järvinen, T.A.H.; Pelto-Huikko, M.; Holli, K.; Isola, J. Estrogen receptor β; is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am. J. Pathol., 2000, 156(1), 29-35.
[http://dx.doi.org/10.1016/S0002-9440(10)64702-5] [PMID: 10623650]
[49]
Porras, L.; Ismail, H.; Mader, S. Positive regulation of estrogen receptor alpha in breast tumorigenesis. Cells, 2021, 10(11), 2966.
[http://dx.doi.org/10.3390/cells10112966] [PMID: 34831189]
[50]
Koehler, K.F.; Helguero, L.A.; Haldosén, L.A.; Warner, M.; Gustafsson, J.Å. Reflections on the discovery and significance of estrogen receptor beta. Endocr. Rev., 2005, 26(3), 465-478.
[http://dx.doi.org/10.1210/er.2004-0027] [PMID: 15857973]
[51]
Balfe, P.; McCann, A.; McGoldrick, A.; McAllister, K.; Kennedy, M.; Dervan, P.; Kerin, M.J. Estrogen receptor α and β; profiling in human breast cancer. Eur. J. Surg. Oncol., 2004, 30(5), 469-474.
[http://dx.doi.org/10.1016/j.ejso.2004.02.010] [PMID: 15135471]
[52]
Shaaban, A.M.; O’Neill, P.A.; Davies, M.P.A.; Sibson, R.; West, C.R.; Smith, P.H.; Foster, C.S. Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am. J. Surg. Pathol., 2003, 27(12), 1502-1512.
[http://dx.doi.org/10.1097/00000478-200312000-00002] [PMID: 14657709]
[53]
Omoto, Y.; Eguchi, H.; Yamamoto-Yamaguchi, Y.; Hayashi, S. Estrogen receptor (ER) β;1 and ERβ;cx/β;2 inhibit ERα function differently in breast cancer cell line MCF7. Oncogene, 2003, 22(32), 5011-5020.
[http://dx.doi.org/10.1038/sj.onc.1206787] [PMID: 12902984]
[54]
Ström, A.; Hartman, J.; Foster, J.S.; Kietz, S.; Wimalasena, J.; Gustafsson, J.Å. Estrogen receptor β; inhibits 17β;-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc. Natl. Acad. Sci. USA, 2004, 101(6), 1566-1571.
[http://dx.doi.org/10.1073/pnas.0308319100] [PMID: 14745018]
[55]
Vitale, D.C.; Piazza, C.; Melilli, B.; Drago, F.; Salomone, S. Isoflavones: estrogenic activity, biological effect and bioavailability. Eur. J. Drug Metab. Pharmacokinet., 2013, 38(1), 15-25.
[http://dx.doi.org/10.1007/s13318-012-0112-y] [PMID: 23161396]
[56]
Mueller, S.O.; Simon, S.; Chae, K.; Metzler, M.; Korach, K.S. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells. Toxicol. Sci., 2004, 80(1), 14-25.
[http://dx.doi.org/10.1093/toxsci/kfh147] [PMID: 15084758]
[57]
Seo, H.S.; DeNardo, D.G.; Jacquot, Y.; Laïos, I.; Vidal, D.S.; Zambrana, C.R.; Leclercq, G.; Brown, P.H. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res. Treat., 2006, 99(2), 121-134.
[http://dx.doi.org/10.1007/s10549-006-9191-2] [PMID: 16541309]
[58]
Pons, D.G.; Vilanova-Llompart, J.; Gaya-Bover, A.; Alorda-Clara, M.; Oliver, J.; Roca, P.; Sastre-Serra, J. The phytoestrogen genistein affects inflammatory-related genes expression depending on the ERα/ERβ; ratio in breast cancer cells. Int. J. Food Sci. Nutr., 2019, 70(8), 941-949.
[http://dx.doi.org/10.1080/09637486.2019.1597025] [PMID: 30945577]
[59]
Harris, D.M.; Besselink, E.; Henning, S.M.; Go, V.L.W.; Heber, D. Phytoestrogens induce differential estrogen receptor alpha- or Beta-mediated responses in transfected breast cancer cells. Exp. Biol. Med. (Maywood), 2005, 230(8), 558-568.
[http://dx.doi.org/10.1177/153537020523000807] [PMID: 16118406]
[60]
An, J.; Tzagarakis-Foster, C.; Scharschmidt, T.C.; Lomri, N.; Leitman, D.C. Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens. J. Biol. Chem., 2001, 276(21), 17808-17814.
[http://dx.doi.org/10.1074/jbc.M100953200] [PMID: 11279159]
[61]
Kostelac, D.; Rechkemmer, G.; Briviba, K. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J. Agric. Food Chem., 2003, 51(26), 7632-7635.
[http://dx.doi.org/10.1021/jf034427b] [PMID: 14664520]
[62]
Morito, K.; Hirose, T.; Kinjo, J.; Hirakawa, T.; Okawa, M.; Nohara, T.; Ogawa, S.; Inoue, S.; Muramatsu, M.; Masamune, Y. Interaction of phytoestrogens with estrogen receptors alpha and beta. Biol. Pharm. Bull., 2001, 24(4), 351-356.
[http://dx.doi.org/10.1248/bpb.24.351] [PMID: 11305594]
[63]
Pons, D.G.; Nadal-Serrano, M.; Blanquer-Rossello, M.M.; Sastre-Serra, J.; Oliver, J.; Roca, P. Genistein modulates proliferation and mitochondrial functionality in breast cancer cells depending on ERalpha/ERbeta ratio. J. Cell. Biochem., 2014, 115(5), 949-958.
[http://dx.doi.org/10.1002/jcb.24737] [PMID: 24375531]
[64]
Sotoca, A.M.; Ratman, D.; van der Saag, P.; Ström, A.; Gustafsson, J.A.; Vervoort, J.; Rietjens, I.M.C.M.; Murk, A.J. Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ERα/ERβ; ratio. J. Steroid Biochem. Mol. Biol., 2008, 112(4-5), 171-178.
[http://dx.doi.org/10.1016/j.jsbmb.2008.10.002] [PMID: 18955141]
[65]
McDonnell, D.P. The molecular determinants of estrogen receptor pharmacology. Maturitas, 2004, 48(Suppl. 1), 7-12.
[http://dx.doi.org/10.1016/j.maturitas.2004.03.006] [PMID: 15337242]
[66]
McCarty, M.F. Isoflavones made simple - Genistein’s agonist activity for the beta-type estrogen receptor mediates their health benefits. Med. Hypotheses, 2006, 66(6), 1093-1114.
[http://dx.doi.org/10.1016/j.mehy.2004.11.046] [PMID: 16513288]
[67]
Dip, R.; Lenz, S.; Antignac, J.P.; Le Bizec, B.; Gmuender, H.; Naegeli, H. Global gene expression profiles induced by phytoestrogens in human breast cancer cells. Endocr. Relat. Cancer, 2008, 15(1), 161-173.
[http://dx.doi.org/10.1677/ERC-07-0252] [PMID: 18310284]
[68]
Carreau, C.; Flouriot, G.; Bennetau-Pelissero, C.; Potier, M. Respective contribution exerted by AF-1 and AF-2 transactivation functions in estrogen receptor α induced transcriptional activity by isoflavones and equol: Consequence on breast cancer cell proliferation. Mol. Nutr. Food Res., 2009, 53(5), 652-658.
[http://dx.doi.org/10.1002/mnfr.200800061] [PMID: 19065587]
[69]
Rice, S.; Whitehead, S.A. Phytoestrogens and breast cancer -promoters or protectors? Endocr. Relat. Cancer, 2006, 13(4), 995-1015.
[http://dx.doi.org/10.1677/erc.1.01159] [PMID: 17158751]
[70]
Dave, B.; Eason, R.R.; Till, S.R.; Geng, Y.; Velarde, M.C.; Badger, T.M.; Simmen, R.C.M. The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis, 2005, 26(10), 1793-1803.
[http://dx.doi.org/10.1093/carcin/bgi131] [PMID: 15905199]
[71]
Shim, H.Y.; Park, J.H.; Paik, H.D.; Nah, S.Y.; Kim, D.S.H.L.; Han, Y.S. Genistein-induced apoptosis of human breast cancer MCF-7 cells involves calpain-caspase and apoptosis signaling kinase 1-p38 mitogen-activated protein kinase activation cascades. Anticancer Drugs, 2007, 18(6), 649-657.
[http://dx.doi.org/10.1097/CAD.0b013e3280825573] [PMID: 17762393]
[72]
Sotoca, A.M.; Gelpke, M.D.; Boeren, S.; Ström, A.; Gustafsson, J.A.; Murk, A.J.; Rietjens, I.M.C.M.; Vervoort, J. Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype- mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol. Cellular Prot., 2011, 10, M110.002170.
[http://dx.doi.org/10.1074/mcp.M110.002170]
[73]
Wang, T.T.Y.; Sathyamoorthy, N.; Phang, J.M. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis, 1996, 17(2), 271-275.
[http://dx.doi.org/10.1093/carcin/17.2.271] [PMID: 8625449]
[74]
Zava, D.T.; Duwe, G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr. Cancer, 1997, 27(1), 31-40.
[http://dx.doi.org/10.1080/01635589709514498] [PMID: 8970179]
[75]
Chen, W.F.; Huang, M.H.; Tzang, C.H.; Yang, M.; Wong, M.S. Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochim. Biophys. Acta Mol. Basis Dis., 2003, 1638(2), 187-196.
[http://dx.doi.org/10.1016/S0925-4439(03)00082-6] [PMID: 12853125]
[76]
Yang, X.; Yang, S.; McKimmey, C.; Liu, B.; Edgerton, S.M.; Bales, W.; Archer, L.T.; Thor, A.D. Genistein induces enhanced growth promotion in ER-positive/erbB-2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/kip1 downregulation. Carcinogenesis, 2010, 31(4), 695-702.
[http://dx.doi.org/10.1093/carcin/bgq007] [PMID: 20067990]
[77]
Ju, Y.H.; Allred, C.D.; Allred, K.F.; Karko, K.L.; Doerge, D.R.; Helferich, W.G. Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. J. Nutr., 2001, 131(11), 2957-2962.
[http://dx.doi.org/10.1093/jn/131.11.2957] [PMID: 11694625]
[78]
Allred, C.D.; Allred, K.F.; Ju, Y.H.; Virant, S.M.; Helferich, W.G. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res., 2001, 61(13), 5045-5050.
[PMID: 11431339]
[79]
Dent, R.; Trudeau, M.; Pritchard, K.I.; Hanna, W.M.; Kahn, H.K.; Sawka, C.A.; Lickley, L.A.; Rawlinson, E.; Sun, P.; Narod, S.A. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer Res., 2007, 13(15), 4429-4434.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-3045] [PMID: 17671126]
[80]
Pan, H.; Zhou, W.; He, W.; Liu, X.; Ding, Q.; Ling, L.; Zha, X.; Wang, S. Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway. Int. J. Mol. Med., 2012, 30(2), 337-343.
[http://dx.doi.org/10.3892/ijmm.2012.990] [PMID: 22580499]
[81]
Shao, Z.M.; Wu, J.; Shen, Z.Z.; Barsky, S.H. Genistein inhibits both constitutive and EGF-stimulated invasion in ER-negative human breast carcinoma cell lines. Anticancer Res., 1998, 18(3A), 1435-1439.
[PMID: 9673352]
[82]
Li, Y.; Upadhyay, S.; Bhuiyan, M.; Sarkar, F.H. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene, 1999, 18(20), 3166-3172.
[http://dx.doi.org/10.1038/sj.onc.1202650] [PMID: 10340389]
[83]
Yang, S.; Zhou, Q.; Yang, X. Caspase-3 status is a determinant of the differential responses to genistein between MDA-MB-231 and MCF-7 breast cancer cells. Biochim. Biophys. Acta Mol. Cell Res., 2007, 1773(6), 903-911.
[http://dx.doi.org/10.1016/j.bbamcr.2007.03.021] [PMID: 17490757]
[84]
Li, Z.; Li, J.; Mo, B.; Hu, C.; Liu, H.; Qi, H.; Wang, X.; Xu, J. Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol. In Vitro, 2008, 22(7), 1749-1753.
[http://dx.doi.org/10.1016/j.tiv.2008.08.001] [PMID: 18761399]
[85]
Santell, R.C.; Kieu, N.; Helferich, W.G. Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice. J. Nutr., 2000, 130(7), 1665-1669.
[http://dx.doi.org/10.1093/jn/130.7.1665] [PMID: 10867033]
[86]
Yang, Z.; Kulkarni, K.; Zhu, W.; Hu, M. Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME. Anticancer. Agents Med. Chem., 2012, 12(10), 1264-1280.
[http://dx.doi.org/10.2174/187152012803833107] [PMID: 22583407]
[87]
Jiang, X.; Patterson, N.M.; Ling, Y.; Xie, J.; Helferich, W.G.; Shapiro, D.J. Low concentrations of the soy phytoestrogen genistein induce proteinase inhibitor 9 and block killing of breast cancer cells by immune cells. Endocrinology, 2008, 149(11), 5366-5373.
[http://dx.doi.org/10.1210/en.2008-0857] [PMID: 18669594]
[88]
Davis, D.D.; Díaz-Cruz, E.S.; Landini, S.; Kim, Y.W.; Brueggemeier, R.W. Evaluation of synthetic isoflavones on cell proliferation, estrogen receptor binding affinity, and apoptosis in human breast cancer cells. J. Steroid Biochem. Mol. Biol., 2008, 108(1-2), 23-31.
[http://dx.doi.org/10.1016/j.jsbmb.2007.07.001] [PMID: 17962013]
[89]
Marik, R.; Allu, M.; Anchoori, R.; Stearns, V.; Umbricht, C.B.; Khan, S. Potent genistein derivatives as inhibitors of estrogen receptor alpha-positive breast cancer. Cancer Biol. Ther., 2011, 11(10), 883-892.
[http://dx.doi.org/10.4161/cbt.11.10.15184] [PMID: 21389782]
[90]
Palkowitz, A.D.; Glasebrook, A.L.; Thrasher, K.J.; Hauser, K.L.; Short, L.L.; Phillips, D.L.; Muehl, B.S.; Sato, M.; Shetler, P.K.; Cullinan, G.J.; Pell, T.R.; Bryant, H.U. Discovery and Synthesis of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[ b]thiophene: A Novel, Highly Potent, Selective Estrogen Receptor Modulator. J. Med. Chem., 1997, 40(10), 1407-1416.
[http://dx.doi.org/10.1021/jm970167b] [PMID: 9154963]
[91]
Förster, C. Mäkela, S.; Wärri, A.; Kietz, S.; Becker, D.; Hultenby, K.; Warner, M.; Gustafsson, J.Å. Involvement of estrogen receptor β; in terminal differentiation of mammary gland epithelium. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15578-15583.
[http://dx.doi.org/10.1073/pnas.192561299] [PMID: 12438700]
[92]
Gemcitabine Hydrochloride and Genistein in Treating Women with Stage IV Breast Cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00244933?term=genistein&cond=breast+cancer&rank=1 (Accessed on: 24 January 2019).
[93]
Wu, A.H.; Spicer, D.; Garcia, A.; Tseng, C.C.; Hovanessian-Larsen, L.; Sheth, P.; Martin, S.E.; Hawes, D.; Russell, C.; MacDonald, H.; Tripathy, D.; Su, M.Y.; Ursin, G.; Pike, M.C. Double-blind randomized 12-month soy intervention had no effects on breast MRI fibroglandular tissue density or mammographic density. Cancer Prev. Res. (Phila.), 2015, 8(10), 942-951.
[http://dx.doi.org/10.1158/1940-6207.CAPR-15-0125] [PMID: 26276750]
[94]
Khan, S.A.; Chatterton, R.T.; Michel, N.; Bryk, M.; Lee, O.; Ivancic, D.; Heinz, R.; Zalles, C.M.; Helenowski, I.B.; Jovanovic, B.D.; Franke, A.A.; Bosland, M.C.; Wang, J.; Hansen, N.M.; Bethke, K.P.; Dew, A.; Coomes, M.; Bergan, R.C. Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial. Cancer Prev. Res. (Phila.), 2012, 5(2), 309-319.
[http://dx.doi.org/10.1158/1940-6207.CAPR-11-0251] [PMID: 22307566]
[95]
Pop, E.A.; Fischer, L.M.; Coan, A.D.; Gitzinger, M.; Nakamura, J.; Zeisel, S.H. Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women. Menopause, 2008, 15(4), 684-692.
[http://dx.doi.org/10.1097/gme.0b013e318167b8f2] [PMID: 18446090]
[96]
Maskarinec, G.; Suzuki, S.; Pagano, I.S.; Morimoto, Y.; Franke, A.A.; Ehya, H. Cytology in nipple aspirate fluid during a randomized soy food intervention among premenopausal women. Nutr. Cancer, 2013, 65(8), 1116-1121.
[http://dx.doi.org/10.1080/01635581.2013.833638] [PMID: 24127645]
[97]
Lamartiniere, C.A. Protection against breast cancer with genistein: a component of soy. Am. J. Clin. Nutr., 2000, 71(6)(Suppl.), 1705S-1707S.
[http://dx.doi.org/10.1093/ajcn/71.6.1705S] [PMID: 10837323]
[98]
Li, Y.; Meeran, S.M.; Patel, S.N.; Chen, H.; Hardy, T.M.; Tollefsbol, T.O. Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer. Mol. Cancer, 2013, 12(1), 9.
[http://dx.doi.org/10.1186/1476-4598-12-9] [PMID: 23379261]
[99]
Kaushik, S.; Shyam, H.; Agarwal, S.; Sharma, R.; Nag, T.C.; Dwivedi, A.K.; Balapure, A.K. Genistein potentiates Centchroman induced antineoplasticity in breast cancer via PI3K/Akt deactivation and ROS dependent induction of apoptosis. Life Sci., 2019, 239, 117073.
[http://dx.doi.org/10.1016/j.lfs.2019.117073] [PMID: 31751581]
[100]
Shukla, R.P.; Dewangan, J.; Urandur, S.; Banala, V.T.; Diwedi, M.; Sharma, S.; Agrawal, S.; Rath, S.K.; Trivedi, R.; Mishra, P.R. Multifunctional hybrid nanoconstructs facilitate intracellular localization of doxorubicin and genistein to enhance apoptotic and anti-angiogenic efficacy in breast adenocarcinoma. Biomater. Sci., 2020, 8(5), 1298-1315.
[http://dx.doi.org/10.1039/C9BM01246J] [PMID: 31903460]

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    • 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
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      • 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
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      220μsalphaeurekaselec_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
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      • 10: 58937999
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      • 13: 58937999
      • 14: 58937999
      • 15: 58937999
      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
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      910μsalphaeurekaselec_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` = 38 limit 1
      1.14msalphaeurekaselec_live_10_06_2022Journal.php#64
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      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=38) and sj.journal_id!=38 group by `j`.`nid`) as `aggregate_table`
      1.73msalphaeurekaselec_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=38) and sj.journal_id!=38 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.5msalphaeurekaselec_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=38) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.41msalphaeurekaselec_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=38) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.53msalphaeurekaselec_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` = '128599'
      250μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 128599
      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` = '128599'
      4.77msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 128599
      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` = '128599' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      5.78msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 128599
      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
      320μsalphaeurekaselec_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
      700μsalphaeurekaselec_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 = 38 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      50.18msalphaeurekaselec_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 = 38 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      16.39msalphaeurekaselec_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 = 38 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      17.96msalphaeurekaselec_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` = 128599 limit 1
      270μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 128599
      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 = 128599 and content_type = 'article' order by status desc limit 1
      330μsalphaeurekaselec_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` = 212359 limit 1
      260μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 212359
      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
      310μsalphaeurekaselec_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` = 'CTMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      500μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CTMC
      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 = '128599' 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) )
      490μsalphaeurekaselec_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 = '12636' 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) )
      560μsalphaeurekaselec_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 = '3330' 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) )
      450μsalphaeurekaselec_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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3330) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3330) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3330)
      8.16msalphaeurekaselec_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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12636) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12636) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12636)
      1.37msalphaeurekaselec_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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128599) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128599) 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 <= 58937999 and j.to_ip >=58937999 )) and ((j.from_date <= 1740472726 and j.to_date >= 1740472726 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128599)
      980μsalphaeurekaselec_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` < '1395' and is_uploaded = 1 and issue_id = 12636 order by cast(first_page as SIGNED) desc limit 1
      530μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1395
      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` > '1413' and is_uploaded = 1 and issue_id = 12636 order by cast(first_page as SIGNED) asc limit 1
      660μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1413
      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'
      260μsalphaeurekaselec_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
      270μsalphaeurekaselec_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` = 128599 limit 1
      3.87msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 128599
      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` = 38 and `b`.`banner_from_date` <= 1740472726 and `b`.`banner_to_date` >= 1740472726 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.16msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740472726
      • 4: 1740472726
      • 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` = 38 and `b`.`banner_from_date` <= 1740472726 and `b`.`banner_to_date` >= 1740472726 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.14msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740472726
      • 4: 1740472726
      • 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='4ac24744d41ad1caeed5055b8f7e7a29'
      240μsalphaeurekaselec_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#?
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        PHPDEBUGBAR_STACK_DATA
        []
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        status_code
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        status_text
        OK
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        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 08:38:46GET/article/128599414361