Review Article

姜黄素:靶向树突状细胞表型和功能的饮食植物化学物质

卷 28, 期 8, 2021

发表于: 15 May, 2020

页: [1549 - 1564] 页: 16

弟呕挨: 10.2174/0929867327666200515101228

价格: $65

摘要

树突状细胞(DC)是连接先天和适应性免疫反应的最强大的抗原呈递细胞。根据于上下文,DC启动免疫反应或促进免疫耐受。它们的表型和功能的任何紊乱都可能引发炎性或自身免疫性疾病。因此,失调的DCs是旨在降低其免疫原性并增强其耐受性的新疗法开发的最有吸引力的药理学靶标。姜黄素是香料姜黄的多酚植物化学成分,具有广泛的药理活性。它以多种方式充当DC的调制器,并将其转换为耐受DC。致耐受性DC具有调节健康和疾病中免疫反应的抗炎和免疫调节活性。姜黄素通过阻断成熟标志物,细胞因子和趋化因子的表达,并破坏DC的抗原呈递机制,使DC对免疫刺激剂无反应或反应低下。它也减少了共刺激分子和粘附分子在DC上的表达,并阻止它们迁移和抗原呈递,但增强了它们的内吞能力。因此,姜黄素会引起DC诱导的调节性T细胞,并抑制CD4 + T辅助物1(Th1),Th2和Th17极化。转录因子(如NF-κB,AP-1,MAPKs(p38,JNK,ERK)和其他细胞内信号分子(如JAK / STAT / SOCS)的抑制为大多数这些观察提供了合理的解释。在这篇综述中,我们总结了姜黄素对DC的表型和功能的潜在影响,DC是协调,刺激和调节免疫反应的关键因素。

关键词: 姜黄素,免疫调节剂,树突状细胞,自身免疫,炎症,硬膜外植物化学物质,树突状细胞。

[1]
Santos, PM; Butterfield, LH Dendritic cell-based cancer vaccines. J. Immunol., 2018, 200(2), 443-449.
[http://dx.doi.org/10.4049/jimmunol.1701024] [PMID: 29311386]
[2]
Sabado, R.L.; Balan, S.; Bhardwaj, N. Dendritic cell-based immunotherapy. Cell Res., 2017, 27(1), 74-95.
[http://dx.doi.org/10.1038/cr.2016.157] [PMID: 28025976]
[3]
Constantino, J.; Gomes, C.; Falcão, A.; Neves, B.M.; Cruz, M.T. Dendritic cell-based immunotherapy: a basic review and recent advances. Immunol. Res., 2017, 65(4), 798-810.
[http://dx.doi.org/10.1007/s12026-017-8931-1] [PMID: 28660480]
[4]
Bol, K.F.; Schreibelt, G.; Gerritsen, W.R.; de Vries, I.J.; Figdor, C.G. Dendritic cell-based immunotherapy: state of the art and beyond. Clin. Cancer Res., 2016, 22(8), 1897-1906.
[http://dx.doi.org/10.1158/1078-0432.ccr-15-1399] [PMID: 27084743]
[5]
Shang, N.; Figini, M.; Shangguan, J.; Wang, B.; Sun, C.; Pan, L.; Ma, Q.; Zhang, Z. Dendritic cells based immunotherapy. Am. J. Cancer Res., 2017, 7(10), 2091-2102.
[PMID: 29119057]
[6]
Panahi, Y.; Hosseini, M.S.; Khalili, N.; Naimi, E.; Simental-Mendía, L.E.; Majeed, M.; Sahebkar, A. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial.Biomed. Pharmacother; , 2016, 82, pp. 578-582.
[http://dx.doi.org/10.1016/j.biopha.2016.05.037] [PMID: 27470399]
[7]
Gupta, S.C.; Patchva, S.; Koh, W.; Aggarwal, B.B. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin. Exp. Pharmacol. Physiol., 2012, 39(3), 283-299.
[http://dx.doi.org/10.1111/j.1440-1681.2011.05648.x] [PMID: 22118895]
[8]
Aggarwal, B.B.; Sung, B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol. Sci., 2009, 30(2), 85-94.
[http://dx.doi.org/10.1016/j.tips.2008.11.002] [PMID: 19110321]
[9]
Mohammadi, A.; Fazeli, B.; Taheri, M.; Sahebkar, A.; Poursina, Z.; Vakili, V. Modulatory effects of curcumin on apoptosis and cytotoxicity-related molecules in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Biomed. Pharmacother., 2017, 85, 457-462.
[http://dx.doi.org/10.1016/j.biopha.2016.11.050] [PMID: 27894665]
[10]
Poursina, Z.; Mohammadi, A.; Yazdi, S.Z.; Humpson, I.; Vakili, V.; Boostani, R.; Rafatpanah, H. Curcumin increased the expression of c-FLIP in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. J. Cell. Biochem., 2019, 120(9), 15740-15745.
[http://dx.doi.org/10.1002/jcb.28843] [PMID: 31074052]
[11]
Panahi, Y.; Kianpour, P.; Mohtashami, R.; Jafari, R.; Simental-Mendía, L.E.; Sahebkar, A. Efficacy and safety of phytosomal curcumin in non-alcoholic fatty liver disease: a randomized controlled trial. Drug Res. (Stuttg.), 2017, 67(4), 244-251.
[http://dx.doi.org/10.1055/s-0043-100019] [PMID: 28158893]
[12]
Abdollahi, E.; Momtazi, A.A.; Johnston, T.P.; Sahebkar, A. Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: a nature-made jack-of-all-trades? J. Cell. Physiol., 2018, 233(2), 830-848.
[http://dx.doi.org/10.1002/jcp.25778] [PMID: 28059453]
[13]
Iranshahi, M.; Sahebkar, A.; Hosseini, S.T.; Takasaki, M.; Konoshima, T.; Tokuda, H. Cancer chemopreventive activity of diversin from Ferula diversivittata in vitro and in vivo. Phytomedicine, 2010, 17(3-4), 269-273.
[http://dx.doi.org/10.1016/j.phymed.2009.05.020] [PMID: 19577457]
[14]
Momtazi, A.A.; Sahebkar, A. Difluorinated curcumin: A promising curcumin analogue with improved anti-tumor activity and pharmacokinetic profile.Curr. Pharmaceut. Design., 22(28), 4386-4397.
[http://dx.doi.org/10.2174/1381612822666160527113501] [PMID: 27229723]
[15]
Mollazadeh, H.; Cicero, A.F.G.; Blesso, C.N.; Pirro, M.; Majeed, M.; Sahebkar, A. Immune modulation by curcumin: the role of interleukin-10. Crit. Rev. Food Sci. Nutr., 2019, 59(1), 89-101.
[http://dx.doi.org/10.1080/10408398.2017.1358139] [PMID: 28799796]
[16]
Rezaee, R.; Momtazi, A.A.; Monemi, A.; Sahebkar, A. Curcumin: A potentially powerful tool to reverse cisplatin-induced toxicity. Pharmacol. Res., 2017, 117, 218-227.
[http://dx.doi.org/10.1016/j.phrs.2016.12.037] [PMID: 28042086]
[17]
Sahebkar, A. Molecular mechanisms for curcumin benefits against ischemic injury. Fertil. Steril., 2010, 94(5), e75-e76.
[http://dx.doi.org/10.1016/j.fertnstert.2010.07.1071] [PMID: 20797714]
[18]
Srivastava, R.M.; Singh, S.; Dubey, S.K.; Misra, K.; Khar, A. Immunomodulatory and therapeutic activity of curcumin. Int. Immunopharmacol., 2011, 11(3), 331-341.
[http://dx.doi.org/10.1016/j.intimp.2010.08.014] [PMID: 20828642]
[19]
Lin, J.K. Molecular targets of curcumin. Adv. Exp. Med. Biol., 2007, 595, 227-243.
[http://dx.doi.org/10.1007/978-0-387-46401-5_10] [PMID: 17569214]
[20]
Zhou, H.; Beevers, C.S.; Huang, S. The targets of curcumin. Curr. Drug Targets, 2011, 12(3), 332-347.
[http://dx.doi.org/10.2174/138945011794815356] [PMID: 20955148]
[21]
Mohammadi, A.; Blesso, C.N.; Barreto, G.E.; Banach, M.; Majeed, M.; Sahebkar, A. Macrophage plasticity, polarization and function in response to curcumin, a diet-derived polyphenol, as an immunomodulatory agent. J. Nutr. Biochem., 2019, 66, 1-16.
[http://dx.doi.org/10.1016/j.jnutbio.2018.12.005] [PMID: 30660832]
[22]
Rahimi, K.; Ahmadi, A.; Hassanzadeh, K.; Soleimani, Z.; Sathyapalan, T.; Mohammadi, A.; Sahebkar, A. Targeting the balance of T helper cell responses by curcumin in inflammatory and autoimmune states. Autoimmun. Rev., 2019, 18(7), 738-748.
[http://dx.doi.org/10.1016/j.autrev.2019.05.012] [PMID: 31059845]
[23]
The Nobel lectures in immunology. The Nobel prize for physiology or medicine, 1908, awarded to Elie Metchnikoff & Paul Ehrlich “in recognition of their work on immunity”. Scand. J. Immunol., 1990, 31(1), 1-13.
[PMID: 2405475]
[24]
Hashimoto, D.; Miller, J.; Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity, 2011, 35(3), 323-335.
[http://dx.doi.org/10.1016/j.immuni.2011.09.007] [PMID: 21943488]
[25]
Mohammadi, A.; Sharifi, A.; Pourpaknia, R.; Mohammadian, S.; Sahebkar, A. Manipulating macrophage polarization and function using classical HDAC inhibitors: Implications for autoimmunity and inflammation. Crit. Rev. Oncol. Hematol., 2018, 128, 1-18.
[http://dx.doi.org/10.1016/j.critrevonc.2018.05.009] [PMID: 29958625]
[26]
Shapouri-Moghaddam, A.; Mohammadian, S.; Vazini, H.; Taghadosi, M.; Esmaeili, S.A.; Mardani, F.; Seifi, B.; Mohammadi, A.; Afshari, J.T.; Sahebkar, A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol., 2018, 233(9), 6425-6440.
[http://dx.doi.org/10.1002/jcp.26429] [PMID: 29319160]
[27]
Momtazi-Borojeni, A.A.; Haftcheshmeh, S.M.; Esmaeili, S-A.; Johnston, T.P.; Abdollahi, E.; Sahebkar, A. Curcumin: a natural modulator of immune cells in systemic lupus erythematosus. Autoimmun. Rev., 2018, 17(2), 125-135.
[http://dx.doi.org/10.1016/j.autrev.2017.11.016] [PMID: 29180127]
[28]
Merad, M.; Sathe, P.; Helft, J.; Miller, J.; Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol., 2013, 31, 563-604.
[http://dx.doi.org/10.1146/annurev-immunol-020711-074950] [PMID: 23516985]
[29]
O’Keeffe, M.; Mok, W.H.; Radford, K.J. Human dendritic cell subsets and function in health and disease. Cell. Mol. Life Sci., 2015, 72(22), 4309-4325.
[http://dx.doi.org/10.1007/s00018-015-2005-0] [PMID: 26243730]
[30]
Geissmann, F.; Manz, M.G.; Jung, S.; Sieweke, M.H.; Merad, M.; Ley, K. Development of monocytes, macrophages, and dendritic cells. Science, 2010, 327(5966), 656-661.
[http://dx.doi.org/10.1126/science.1178331] [PMID: 20133564]
[31]
Liu, J.; Cao, X. Regulatory dendritic cells in autoimmunity: A comprehensive review. J. Autoimmun., 2015, 63, 1-12.
[http://dx.doi.org/10.1016/j.jaut.2015.07.011] [PMID: 26255250]
[32]
Takenaka, M.C.; Quintana, F.J. Tolerogenic dendritic cells. Semin. Immunopathol., 2017, 39(2), 113-120.
[http://dx.doi.org/10.1007/s00281-016-0587-8] [PMID: 27646959]
[33]
Rea, D.; van Kooten, C.; van Meijgaarden, K.E.; Ottenhoff, T.H.; Melief, C.J.; Offringa, R. Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. Blood, 2000, 95(10), 3162-3167.
[http://dx.doi.org/10.1182/blood.V95.10.3162] [PMID: 10807783]
[34]
Moser, M.; De Smedt, T.; Sornasse, T.; Tielemans, F.; Chentoufi, A.A.; Muraille, E.; Van Mechelen, M.; Urbain, J.; Leo, O. Glucocorticoids down-regulate dendritic cell function in vitro and in vivo. Eur. J. Immunol., 1995, 25(10), 2818-2824.
[http://dx.doi.org/10.1002/eji.1830251016] [PMID: 7589077]
[35]
Matasić, R.; Dietz, A.B.; Vuk-Pavlović, S. Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J. Leukoc. Biol., 1999, 66(6), 909-914.
[http://dx.doi.org/10.1002/jlb.66.6.909] [PMID: 10614771]
[36]
Berer, A.; Stöckl, J.; Majdic, O.; Wagner, T.; Kollars, M.; Lechner, K.; Geissler, K.; Oehler, L. 1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. Exp. Hematol., 2000, 28(5), 575-583.
[http://dx.doi.org/10.1016/S0301-472X(00)00143-0] [PMID: 10812248]
[37]
Xie, Z.; Chen, J.; Zheng, C.; Wu, J.; Cheng, Y.; Zhu, S.; Lin, C.; Cao, Q.; Zhu, J.; Jin, T. 1,25-dihydroxyvitamin D3 -induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells. Immunology, 2017, 152(3), 414-424.
[http://dx.doi.org/10.1111/imm.12776] [PMID: 28617989]
[38]
Adorini, L.; Penna, G. Induction of tolerogenic dendritic cells by vitamin D receptor agonists. Handb. Exp. Pharmacol., 2009, (188), 251-273.
[http://dx.doi.org/10.1007/978-3-540-71029-5_12] [PMID: 19031030]
[39]
Ferreira, G.B.; Kleijwegt, F.S.; Waelkens, E.; Lage, K.; Nikolic, T.; Hansen, D.A.; Workman, C.T.; Roep, B.O.; Overbergh, L.; Mathieu, C. Differential protein pathways in 1,25-dihydroxyvitamin d(3) and dexamethasone modulated tolerogenic human dendritic cells. J. Proteome Res., 2012, 11(2), 941-971.
[http://dx.doi.org/10.1021/pr200724e] [PMID: 22103328]
[40]
Penna, G; Adorini, L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. (Baltimore, Md : 1950)., 2000, 164(5), 2405-2411.
[41]
Canning, M.O.; Grotenhuis, K.; de Wit, H.; Ruwhof, C.; Drexhage, H.A. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur. J. Endocrinol., 2001, 145(3), 351-357.
[http://dx.doi.org/10.1530/eje.0.1450351] [PMID: 11517017]
[42]
Ferreira, G.B.; Overbergh, L.; Verstuyf, A.; Mathieu, C. 1α,25-Dihydroxyvitamin D3 and its analogs as modulators of human dendritic cells: a comparison dose-titration study. J. Steroid Biochem. Mol. Biol., 2013, 136, 160-165.
[http://dx.doi.org/10.1016/j.jsbmb.2012.10.009] [PMID: 23098690]
[43]
Gregori, S.; Casorati, M.; Amuchastegui, S.; Smiroldo, S.; Davalli, A.M.; Adorini, L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol., 2001, 167(4), 1945-1953.
[http://dx.doi.org/10.4049/jimmunol.167.4.1945] [PMID: 11489974]
[44]
Mehling, A.; Grabbe, S.; Voskort, M.; Schwarz, T.; Luger, T.A.; Beissert, S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J. Immunol., 2000, 165(5), 2374-2381.
[http://dx.doi.org/10.4049/jimmunol.165.5.2374] [PMID: 10946260]
[45]
Colic, M.; Stojic-Vukanic, Z.; Pavlovic, B.; Jandric, D.; Stefanoska, I. Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells. Clin. Exp. Immunol., 2003, 134(1), 63-69.
[http://dx.doi.org/10.1046/j.1365-2249.2003.02269.x] [PMID: 12974756]
[46]
Turnquist, H.R.; Raimondi, G.; Zahorchak, A.F.; Fischer, R.T.; Wang, Z.; Thomson, A.W. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J. Immunol., 2007, 178(11), 7018-7031.
[http://dx.doi.org/10.4049/jimmunol.178.11.7018] [PMID: 17513751]
[47]
Horibe, E.K.; Sacks, J.; Unadkat, J.; Raimondi, G.; Wang, Z.; Ikeguchi, R.; Marsteller, D.; Ferreira, L.M.; Thomson, A.W.; Lee, W.P.; Feili-Hariri, M. Rapamycin-conditioned, alloantigen-pulsed dendritic cells promote indefinite survival of vascularized skin allografts in association with T regulatory cell expansion. Transpl. Immunol., 2008, 18(4), 307-318.
[http://dx.doi.org/10.1016/j.trim.2007.10.007] [PMID: 18158116]
[48]
Hackstein, H.; Taner, T.; Zahorchak, A.F.; Morelli, A.E.; Logar, A.J.; Gessner, A.; Thomson, A.W. Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood, 2003, 101(11), 4457-4463.
[http://dx.doi.org/10.1182/blood-2002-11-3370] [PMID: 12531798]
[49]
Hackstein, H.; Morelli, A.E.; Larregina, A.T.; Ganster, R.W.; Papworth, G.D.; Logar, A.J. Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. J. Immunol., 2001, 166(12), 7053-7062.
[http://dx.doi.org/10.4049/jimmunol.166.12.7053] [PMID: 11390449]
[50]
Buckland, M.; Jago, C.; Fazekesova, H.; George, A.; Lechler, R.; Lombardi, G. Aspirin modified dendritic cells are potent inducers of allo-specific regulatory T-cells. Int. Immunopharmacol., 2006, 6(13-14), 1895-1901.
[http://dx.doi.org/10.1016/j.intimp.2006.07.008] [PMID: 17219690]
[51]
Matasic, R.; Dietz, A.B.; Vuk-Pavlovic, S. Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin. Immunology, 2000, 101(1), 53-60.
[http://dx.doi.org/10.1046/j.1365-2567.2000.00065.x] [PMID: 11012753]
[52]
Cai, D.T.; Ho, Y.H.; Chiow, K.H.; Wee, S.H.; Han, Y.; Peh, M.T.; Wong, S.H. Aspirin regulates SNARE protein expression and phagocytosis in dendritic cells. Mol. Membr. Biol., 2011, 28(2), 90-102.
[http://dx.doi.org/10.3109/09687688.2010.525756] [PMID: 21231793]
[53]
Verhasselt, V.; Vanden Berghe, W.; Vanderheyde, N.; Willems, F.; Haegeman, G.; Goldman, M. N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. J. Immunol., 1999, 162(5), 2569-2574.
[PMID: 10072497]
[54]
Millard, A.L.; Mertes, P.M.; Ittelet, D.; Villard, F.; Jeannesson, P.; Bernard, J. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin. Exp. Immunol., 2002, 130(2), 245-255.
[http://dx.doi.org/10.1046/j.0009-9104.2002.01977.x] [PMID: 12390312]
[55]
Liu, L.; Li, L.; Min, J.; Wang, J.; Wu, H.; Zeng, Y.; Chen, S.; Chu, Z. Butyrate interferes with the differentiation and function of human monocyte-derived dendritic cells. Cell. Immunol., 2012, 277(1-2), 66-73.
[http://dx.doi.org/10.1016/j.cellimm.2012.05.011] [PMID: 22698927]
[56]
Wang, B.; Morinobu, A.; Horiuchi, M.; Liu, J.; Kumagai, S. Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell. Immunol., 2008, 253(1-2), 54-58.
[http://dx.doi.org/10.1016/j.cellimm.2008.04.016] [PMID: 18522857]
[57]
Li, J.; Li, J.; Zhang, F. The immunoregulatory effects of Chinese herbal medicine on the maturation and function of dendritic cells. J. Ethnopharmacol., 2015, 171, 184-195.
[http://dx.doi.org/10.1016/j.jep.2015.05.050] [PMID: 26068430]
[58]
Aldahlawi, A.M. Modulation of dendritic cell immune functions by plant components. J. Micros. Ultrastruct., 2016, 4(2), 55-62.
[http://dx.doi.org/10.1016/j.jmau.2016.01.001] [PMID: 30023210]
[59]
Ebadi, P.; Karimi, M.H.; Amirghofran, Z. Plant components for immune modulation targeting dendritic cells: implication for therapy. Immunotherapy, 2014, 6(10), 1037-1053.
[http://dx.doi.org/10.2217/imt.14.77] [PMID: 25428644]
[60]
Rogers, N.M.; Kireta, S.; Coates, P.T. Curcumin induces maturation-arrested dendritic cells that expand regulatory T cells in vitro and in vivo. Clin. Exp. Immunol., 2010, 162(3), 460-473.
[http://dx.doi.org/10.1111/j.1365-2249.2010.04232.x] [PMID: 21070208]
[61]
Kim, G-Y.; Kim, K-H.; Lee, S-H.; Yoon, M-S.; Lee, H-J.; Moon, D-O. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J. Immunol., 2005, 174(12), 8116-8124.
[http://dx.doi.org/10.4049/jimmunol.174.12.8116] [PMID: 15944320]
[62]
Shirley, S.A.; Montpetit, A.J.; Lockey, R.F.; Mohapatra, S.S. Curcumin prevents human dendritic cell response to immune stimulants. Biochem. Biophys. Res. Commun., 2008, 374(3), 431-436.
[http://dx.doi.org/10.1016/j.bbrc.2008.07.051] [PMID: 18639521]
[63]
Krasovsky, J.; Chang, D.H.; Deng, G.; Yeung, S.; Lee, M.; Leung, P.C.; Cunningham-Rundles, S.; Cassileth, B.; Dhodapkar, M.V. Inhibition of human dendritic cell activation by hydroethanolic but not lipophilic extracts of turmeric (Curcuma longa). Planta Med., 2009, 75(4), 312-315.
[http://dx.doi.org/10.1055/s-0028-1088367] [PMID: 19034830]
[64]
Kumar, A.; Dhawan, S.; Hardegen, N.J.; Aggarwal, B.B. Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem. Pharmacol., 1998, 55(6), 775-783.
[http://dx.doi.org/10.1016/S0006-2952(97)00557-1] [PMID: 9586949]
[65]
Sandur, S.K.; Pandey, M.K.; Sung, B.; Ahn, K.S.; Murakami, A.; Sethi, G.; Limtrakul, P.; Badmaev, V.; Aggarwal, B.B. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis, 2007, 28(8), 1765-1773.
[http://dx.doi.org/10.1093/carcin/bgm123] [PMID: 17522064]
[66]
Sebolt-Leopold, J.S. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene, 2000, 19(56), 6594-6599.
[http://dx.doi.org/10.1038/sj.onc.1204083] [PMID: 11426644]
[67]
Seger, R.; Krebs, E.G. The MAPK signaling cascade. FASEB J., 1995, 9(9), 726-735.
[http://dx.doi.org/10.1096/fasebj.9.9.7601337] [PMID: 7601337]
[68]
Singh, S.; Aggarwal, B.B. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem., 1995, 270(42), 24995-25000.
[http://dx.doi.org/10.1074/jbc.270.42.24995] [PMID: 7559628]
[69]
Arrighi, J.F.; Rebsamen, M.; Rousset, F.; Kindler, V.; Hauser, C. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J. Immunol., 2001, 166(6), 3837-3845.
[http://dx.doi.org/10.4049/jimmunol.166.6.3837] [PMID: 11238627]
[70]
An, H.; Yu, Y.; Zhang, M.; Xu, H.; Qi, R.; Yan, X.; Liu, S.; Wang, W.; Guo, Z.; Guo, J.; Qin, Z.; Cao, X. Involvement of ERK, p38 and NF-kappaB signal transduction in regulation of TLR2, TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritic cells. Immunology, 2002, 106(1), 38-45.
[http://dx.doi.org/10.1046/j.1365-2567.2002.01401.x] [PMID: 11972630]
[71]
Bharti, A.C.; Donato, N.; Singh, S.; Aggarwal, B.B. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood, 2003, 101(3), 1053-1062.
[http://dx.doi.org/10.1182/blood-2002-05-1320] [PMID: 12393461]
[72]
O’Shea, J.J.; Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity, 2012, 36(4), 542-550.
[http://dx.doi.org/10.1016/j.immuni.2012.03.014] [PMID: 22520847]
[73]
Huang, R-Y.; Yu, Y-L.; Cheng, W-C.; OuYang, C-N.; Fu, E.; Chu, C-L. Immunosuppressive effect of quercetin on dendritic cell activation and function. J. Immunol., 2010, 184(12), 6815-6821.
[http://dx.doi.org/10.4049/jimmunol.0903991] [PMID: 20483746]
[74]
Kahkhaie, K.R.; Mirhosseini, A.; Aliabadi, A.; Mohammadi, A.; Mosavi, M.J.; Haftcheshmeh, S.M. Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology, 2019, 27(5), 885-900.
[http://dx.doi.org/10.1007/s10787-019-00607-3 ] [PMID: 31140036]
[75]
Zhao, H-M.; Xu, R.; Huang, X-Y.; Cheng, S-M.; Huang, M-F.; Yue, H-Y.; Wang, X.; Zou, Y.; Lu, A.P.; Liu, D.Y. curcumin suppressed activation of dendritic cells via JAK/STAT/SOCS signal in mice with experimental colitis. Front. Pharmacol., 2016, 7(455), 455.
[http://dx.doi.org/10.3389/fphar.2016.00455] [PMID: 27932984]
[76]
Renkl, A.C.; Wussler, J.; Ahrens, T.; Thoma, K.; Kon, S.; Uede, T.; Martin, S.F.; Simon, J.C.; Weiss, J.M. Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype. Blood, 2005, 106(3), 946-955.
[http://dx.doi.org/10.1182/blood-2004-08-3228] [PMID: 15855273]
[77]
Cantor, H.; Shinohara, M.L. Regulation of T-helper-cell lineage development by osteopontin: the inside story. Nat. Rev. Immunol., 2009, 9(2), 137-141.
[http://dx.doi.org/10.1038/nri2460] [PMID: 19096390]
[78]
O’Regan, A.W.; Chupp, G.L.; Lowry, J.A.; Goetschkes, M.; Mulligan, N.; Berman, J.S. Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J. Immunol., 1999, 162(2), 1024-1031.
[PMID: 9916729]
[79]
Koguchi, Y.; Kawakami, K.; Uezu, K.; Fukushima, K.; Kon, S.; Maeda, M.; Nakamoto, A.; Owan, I.; Kuba, M.; Kudeken, N.; Azuma, M.; Yara, S.; Shinzato, T.; Higa, F.; Tateyama, M.; Kadota, J.; Mukae, H.; Kohno, S.; Uede, T.; Saito, A. High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 T helper cell response in tuberculosis. Am. J. Respir. Crit. Care Med., 2003, 167(10), 1355-1359.
[http://dx.doi.org/10.1164/rccm.200209-1113OC] [PMID: 12574077]
[80]
Xu, G.; Nie, H.; Li, N.; Zheng, W.; Zhang, D.; Feng, G.; Ni, L.; Xu, R.; Hong, J.; Zhang, J.Z. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J. Clin. Invest., 2005, 115(4), 1060-1067.
[http://dx.doi.org/10.1172/JCI200523273] [PMID: 15761492]
[81]
Kourepini, E.; Aggelakopoulou, M.; Alissafi, T.; Paschalidis, N.; Simoes, D.C.; Panoutsakopoulou, V. Osteopontin expression by CD103- dendritic cells drives intestinal inflammation. Proc. Natl. Acad. Sci. USA, 2014, 111(9), E856-E865.
[http://dx.doi.org/10.1073/pnas.1316447111] [PMID: 24550510]
[82]
Sato, T.; Nakai, T.; Tamura, N.; Okamoto, S.; Matsuoka, K.; Sakuraba, A.; Fukushima, T.; Uede, T.; Hibi, T. Osteopontin/Eta-1 upregulated in Crohn’s disease regulates the Th1 immune response. Gut, 2005, 54(9), 1254-1262.
[http://dx.doi.org/10.1136/gut.2004.048298] [PMID: 16099792]
[83]
Comabella, M.; Pericot, I.; Goertsches, R.; Nos, C.; Castillo, M.; Blas Navarro, J.; Río, J.; Montalban, X. Plasma osteopontin levels in multiple sclerosis. J. Neuroimmunol., 2005, 158(1-2), 231-239.
[http://dx.doi.org/10.1016/j.jneuroim.2004.09.004] [PMID: 15589058]
[84]
Murugaiyan, G.; Mittal, A.; Weiner, H.L. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J. Immunol., 2008, 181(11), 7480-7488.
[http://dx.doi.org/10.4049/jimmunol.181.11.7480] [PMID: 19017937]
[85]
Lv, J.; Shao, Q.; Wang, H.; Shi, H.; Wang, T.; Gao, W.; Song, B.; Zheng, G.; Kong, B.; Qu, X. Effects and mechanisms of curcumin and basil polysaccharide on the invasion of SKOV3 cells and dendritic cells. Mol. Med. Rep., 2013, 8(5), 1580-1586.
[http://dx.doi.org/10.3892/mmr.2013.1695] [PMID: 24065177]
[86]
Chen, Y.J.; Wei, Y.Y.; Chen, H.T.; Fong, Y.C.; Hsu, C.J.; Tsai, C.H.; Hsu, H.C.; Liu, S.H.; Tang, C.H. Osteopontin increases migration and MMP-9 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. J. Cell. Physiol., 2009, 221(1), 98-108.
[http://dx.doi.org/10.1002/jcp.21835] [PMID: 19475568]
[87]
Yang, G.; Zhang, Y.; Wu, J.; Xiong, J.; Deng, H.; Wang, J.; Yang, C.; Zhu, Z. Osteopontin regulates growth and migration of human nasopharyngeal cancer cells. Mol. Med. Rep., 2011, 4(6), 1169-1173.
[http://dx.doi.org/10.3892/mmr.2011.538] [PMID: 21785824]
[88]
Philip, S.; Kundu, G.C. Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J. Biol. Chem., 2003, 278(16), 14487-14497.
[http://dx.doi.org/10.1074/jbc.M207309200] [PMID: 12473670]
[89]
Walsh, K.P.; Mills, K.H. Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol., 2013, 34(11), 521-530.
[http://dx.doi.org/10.1016/j.it.2013.07.006] [PMID: 23973621]
[90]
Raphael, I.; Nalawade, S.; Eagar, T.N.; Forsthuber, T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine, 2015, 74(1), 5-17.
[http://dx.doi.org/10.1016/j.cyto.2014.09.011] [PMID: 25458968]
[91]
Peron, G.; de Lima Thomaz, L.; Camargo da Rosa, L.; Thomé, R.; Cardoso Verinaud, L.M. Modulation of dendritic cell by pathogen antigens: Where do we stand? Immunol. Lett., 2018, 196, 91-102.
[http://dx.doi.org/10.1016/j.imlet.2018.02.001] [PMID: 29427742]
[92]
Cong, Y.; Wang, L.; Konrad, A.; Schoeb, T.; Elson, C.O. Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cells. Eur. J. Immunol., 2009, 39(11), 3134-3146.
[http://dx.doi.org/10.1002/eji.200939052] [PMID: 19839007]
[93]
Yoneyama, S.; Kawai, K.; Tsuno, N.H.; Okaji, Y.; Asakage, M.; Tsuchiya, T.; Yamada, J.; Sunami, E.; Osada, T.; Kitayama, J.; Takahashi, K.; Nagawa, H. Epigallocatechin gallate affects human dendritic cell differentiation and maturation. J. Allergy Clin. Immunol., 2008, 121(1), 209-214.
[http://dx.doi.org/10.1016/j.jaci.2007.08.026] [PMID: 17935769]
[94]
Svajger, U.; Obermajer, N.; Jeras, M. Dendritic cells treated with resveratrol during differentiation from monocytes gain substantial tolerogenic properties upon activation. Immunology, 2010, 129(4), 525-535.
[http://dx.doi.org/10.1111/j.1365-2567.2009.03205.x] [PMID: 20002210]
[95]
Yang, X.; Lv, J-N.; Li, H.; Jiao, B.; Zhang, Q.H.; Zhang, Y. Curcumin reduces lung inflammation via Wnt/beta-catenin signaling in mouse model of asthma. J. Asthma, 2017, 54(4), 335-340.
[http://dx.doi.org/10.1080/02770903.2016.1218018] [PMID: 27715343]
[96]
Jung, I.D.; Lee, C.M.; Jeong, Y.I.; Lee, J.S.; Park, W.S.; Han, J.; Park, Y.M. Differential regulation of indoleamine 2,3-dioxygenase by lipopolysaccharide and interferon gamma in murine bone marrow derived dendritic cells. FEBS Lett., 2007, 581(7), 1449-1456.
[http://dx.doi.org/10.1016/j.febslet.2007.02.073] [PMID: 17367785]
[97]
Mellor, A.L.; Lemos, H.; Huang, L. Indoleamine 2,3-dioxygenase and tolerance: where are we now? Front. Immunol., 2017, 8, 1360.
[http://dx.doi.org/10.3389/fimmu.2017.01360] [PMID: 29163470]
[98]
Mellor, A.L.; Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol., 2004, 4(10), 762-774.
[http://dx.doi.org/10.1038/nri1457] [PMID: 15459668]
[99]
Lemos, H.; Huang, L.; Prendergast, G.C.; Mellor, A.L. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat. Rev. Cancer, 2019, 19(3), 162-175.
[http://dx.doi.org/10.1038/s41568-019-0106-z] [PMID: 30696923]
[100]
Jung, I.D.; Jeong, Y.I.; Lee, C.M.; Noh, K.T.; Jeong, S.K.; Chun, S.H.; Choi, O.H.; Park, W.S.; Han, J.; Shin, Y.K.; Kim, H.W.; Yun, C.H.; Park, Y.M. COX-2 and PGE2 signaling is essential for the regulation of IDO expression by curcumin in murine bone marrow-derived dendritic cells. Int. Immunopharmacol., 2010, 10(7), 760-768.
[http://dx.doi.org/10.1016/j.intimp.2010.04.006] [PMID: 20399909]
[101]
Jeong, Y.I.; Kim, S.W.; Jung, I.D.; Lee, J.S.; Chang, J.H.; Lee, C.M.; Chun, S.H.; Yoon, M.S.; Kim, G.T.; Ryu, S.W.; Kim, J.S.; Shin, Y.K.; Lee, W.S.; Shin, H.K.; Lee, J.D.; Park, Y.M. Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. J. Biol. Chem., 2009, 284(6), 3700-3708.
[http://dx.doi.org/10.1074/jbc.M807328200] [PMID: 19075017]
[102]
Vilekar, P.; Awasthi, S.; Natarajan, A.; Anant, S.; Awasthi, V. EF24 suppresses maturation and inflammatory response in dendritic cells. Int. Immunol., 2012, 24(7), 455-464.
[http://dx.doi.org/10.1093/intimm/dxr121] [PMID: 22378503]
[103]
Cho, J.W.; Lee, K.S.; Kim, C.W. Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int. J. Mol. Med., 2007, 19(3), 469-474.
[PMID: 17273796]
[104]
Seifarth, C.C.; Hinkmann, C.; Hahn, E.G.; Lohmann, T.; Harsch, I.A. Reduced frequency of peripheral dendritic cells in type 2 diabetes. Exp. Clin. Endocrinol. Diabetes, 2008, 116(3), 162-166.
[http://dx.doi.org/10.1055/s-2007-990278] [PMID: 18213547]
[105]
Mráz, M.; Cinkajzlová, A.; Kloučková, J.; Lacinová, Z.; Kratochvílová, H.; Lipš, M.; Pořízka, M.; Kopecký, P.; Lindner, J.; Kotulák, T.; Netuka, I.; Haluzík, M. Dendritic cells in subcutaneous and epicardial adipose tissue of subjects with type 2 diabetes, obesity, and coronary artery disease. Mediators Inflamm., 2019.20195481725
[http://dx.doi.org/10.1155/2019/5481725] [PMID: 31210749]
[106]
Yekollu, S.K.; Thomas, R.; O’Sullivan, B. Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice. Diabetes, 2011, 60(11), 2928-2938.
[http://dx.doi.org/10.2337/db11-0275] [PMID: 21885868]
[107]
Steinbach, E.C.; Plevy, S.E. The role of macrophages and dendritic cells in the initiation of inflammation in IBD. Inflamm. Bowel Dis., 2014, 20(1), 166-175.
[http://dx.doi.org/10.1097/MIB.0b013e3182a69dca] [PMID: 23974993]
[108]
Bates, J.; Diehl, L. Dendritic cells in IBD pathogenesis: an area of therapeutic opportunity? J. Pathol., 2014, 232(2), 112-120.
[http://dx.doi.org/10.1002/path.4277] [PMID: 24122796]
[109]
Beloqui, A.; Memvanga, P.B.; Coco, R.; Reimondez-Troitiño, S.; Alhouayek, M.; Muccioli, G.G.; Alonso, M.J.; Csaba, N.; de la Fuente, M.; Préat, V. A comparative study of curcumin-loaded lipid-based nanocarriers in the treatment of inflammatory bowel disease. Colloids Surf. B Biointerfaces, 2016, 143, 327-335.
[http://dx.doi.org/10.1016/j.colsurfb.2016.03.038] [PMID: 27022873]
[110]
Hanai, H.; Sugimoto, K. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Curr. Pharm. Des., 2009, 15(18), 2087-2094.
[http://dx.doi.org/10.2174/138161209788489177] [PMID: 19519446]
[111]
Sreedhar, R.; Arumugam, S.; Thandavarayan, R.A.; Karuppagounder, V.; Watanabe, K. Curcumin as a therapeutic agent in the chemoprevention of inflammatory bowel disease. Drug Discov. Today, 2016, 21(5), 843-849.
[http://dx.doi.org/10.1016/j.drudis.2016.03.007] [PMID: 26995272]
[112]
Baliga, M.S.; Joseph, N.; Venkataranganna, M.V.; Saxena, A.; Ponemone, V.; Fayad, R. Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations. Food Funct., 2012, 3(11), 1109-1117.
[http://dx.doi.org/10.1039/c2fo30097d] [PMID: 22833299]
[113]
Vecchi Brumatti, L.; Marcuzzi, A.; Tricarico, P.M.; Zanin, V.; Girardelli, M.; Bianco, A.M. Curcumin and inflammatory bowel disease: potential and limits of innovative treatments. Molecules, 2014, 19(12), 21127-21153.
[http://dx.doi.org/10.3390/molecules191221127] [PMID: 25521115]
[114]
Larmonier, C.B.; Uno, J.K.; Lee, K.M.; Karrasch, T.; Laubitz, D.; Thurston, R.; Midura-Kiela, M.T.; Ghishan, F.K.; Sartor, R.B.; Jobin, C.; Kiela, P.R. Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection. Am. J. Physiol. Gastrointest. Liver Physiol., 2008, 295(5), G1079-G1091.
[http://dx.doi.org/10.1152/ajpgi.90365.2008] [PMID: 18818316]
[115]
Zhao, H-M.; Xu, R.; Huang, X-Y.; Cheng, S-M.; Huang, M-F.; Yue, H-Y.; Wang, X.; Zou, Y.; Lu, A.P.; Liu, D.Y. Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice. World J. Gastroenterol., 2016, 22(23), 5374-5383.
[http://dx.doi.org/10.3748/wjg.v22.i23.5374] [PMID: 27340353]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version467msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[02:56:07] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[02:56:08] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[02:56:08] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[02:56:08] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (100ms)time
  • Application (367ms)time
  • 1 x Application (78.54%)
    367ms
    1 x Booting (21.45%)
    100ms
    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
    41 statements were executed, 4 of which were duplicates, 37 unique. Show only duplicated294ms
    • 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 ('316574772','',1,1739847367,1739847367) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739847367
      960μsalphaeurekaselec_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 ('316574772','/article/106647/cn',1,1739847367,1739847367)
      140μsalphaeurekaselec_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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) 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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) 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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) 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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) 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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) 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 >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316574772 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316574772) limit 1
      13.52msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316574772
      • 1: 316574772
      • 2: 316574772
      • 3: 316574772
      • 4: 316574772
      • 5: 316574772
      • 6: 316574772
      • 7: 316574772
      • 8: 316574772
      • 9: 316574772
      • 10: 316574772
      • 11: 316574772
      • 12: 316574772
      • 13: 316574772
      • 14: 316574772
      • 15: 316574772
      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=106647
      810μsalphaeurekaselec_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
      860μsalphaeurekaselec_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`
      1.56msalphaeurekaselec_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
      1.27msalphaeurekaselec_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`
      3.61msalphaeurekaselec_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
      2.99msalphaeurekaselec_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` = '106647'
      300μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 106647
      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` = '106647'
      3.78msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 106647
      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` = '106647' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.2msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 106647
      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
      270μsalphaeurekaselec_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
      490μsalphaeurekaselec_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
      31.87msalphaeurekaselec_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
      75.87msalphaeurekaselec_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
      106msalphaeurekaselec_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` = 106647 limit 1
      260μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 106647
      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 = 106647 and content_type = 'article' order by status desc limit 1
      1.3msalphaeurekaselec_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 a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 472 and content_id!=106647 and cd.content_type = 'article' order by rand() limit 20
      13.49msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 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` = 181978 limit 1
      310μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 181978
      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
      290μsalphaeurekaselec_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
      470μsalphaeurekaselec_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 = '106647' 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) )
      550μsalphaeurekaselec_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 = '10611' 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) )
      410μsalphaeurekaselec_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 = '2916' 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) )
      390μsalphaeurekaselec_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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2916)
      7.98msalphaeurekaselec_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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10611) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10611) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10611)
      820μsalphaeurekaselec_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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 106647) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 106647) 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 <= 316574772 and j.to_ip >=316574772 )) and ((j.from_date <= 1739847368 and j.to_date >= 1739847368 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 106647)
      810μsalphaeurekaselec_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` < '1549' and is_uploaded = 1 and issue_id = 10611 order by cast(first_page as SIGNED) desc limit 1
      630μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1549
      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` > '1564' and is_uploaded = 1 and issue_id = 10611 order by cast(first_page as SIGNED) asc limit 1
      580μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1564
      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` = 'cn'
      180μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 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` = 2
      180μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 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 `multilanguage_article` where (`language_id` = 2 and `article_id` = 106647)
      5.69msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 106647
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 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
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 106647)
      2.4msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 106647
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 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 CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (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 `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 106647 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      5.66msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 106647
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 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 `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 25 and `language_id` = 2
      250μsalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 25
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 106647 limit 1
      2.68msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 106647
      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` <= 1739847368 and `b`.`banner_to_date` >= 1739847368 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: 25
      • 3: 1739847368
      • 4: 1739847368
      • 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` <= 1739847368 and `b`.`banner_to_date` >= 1739847368 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.12msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1739847368
      • 4: 1739847368
      • 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='f26464b8d6e7158187e2d4764f30f16d'
      190μsalphaeurekaselec_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\MultiLangArticle
    2MultiLangArticle.php#?
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        izVem1Aa2rr5CNnKzqM48GkCXDYkweLtteG9JNc6
        uc_cart_id
        f26464b8d6e7158187e2d4764f30f16d
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/106647/cn" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/106647/cn
        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:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6ImxWSTZhNWhnRWs3ZG9rOVg4ZXhBcXc9PSIsInZhbHVlIjoiZms0czlWdkdFaTB1WTRRMkVGYzRtMjBNWGhpT1o5STZVWndVM0EyZHUxQT0iLCJtYWMiOiI1OWZlNDgxMDk2ZWY5NTZlZmY2MzE1NjkzMGU5MTI5ZmM4MTYwZjg5NWY3NDM2NGNiZDQxNGIxMjQ3Yzk3NThhIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6ImxWSTZhNWhnRWs3ZG9rOVg4ZXhBcXc9PSIsInZhbHVlIjoiZms0czlWdkdFaTB1WTRRMkVGYzRtMjBNWGhpT1o5STZVWndVM0EyZHUxQT0iLCJtYWMiOiI1OWZlNDgxMDk2ZWY5" ] "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
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        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, 18 Feb 2025 02:56:08 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im93VCttRE96dzV1UE9FeWZXZWczeFE9PSIsInZhbHVlIjoiUlN1SERaM0ZWVmdrOW1ZZ2dJMkVKMVpHdkZKZmRqTXdLYzBBQVlaNjBSYmNHNTlBdjhtY3VZeHBITlprVnJoTkZmR3lSV2w3WVFvNjJmcHUwR2wrcklXeGNiT1k5RWpLQU5JOG5JUWM1V3dya3lSRkV3b0ZQeTJHdmw5UkpnMFciLCJtYWMiOiI3NDZjOWQyNWQ1ZjVjNzI1ZGIxZTIyMDlkYTAwNzhkMzE3MzdjMDczNWY1ZGY4MjNlZjEzMmViNGE4ZDk2ZWQ3IiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 14:56:08 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Im93VCttRE96dzV1UE9FeWZXZWczeFE9PSIsInZhbHVlIjoiUlN1SERaM0ZWVmdrOW1ZZ2dJMkVKMVpHdkZKZmRqTXdLYzBBQVlaNjBSYmNHNTlBdjhtY3VZeHBITlprVnJoTkZmR3lSV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkhJMnljM2ZVdFZ3VVNidFZ4ZDFYUlE9PSIsInZhbHVlIjoia2VhanhrNXFLM2VGQmJhQXJqRGtuV3d0TG1KUGNKS3liT3lkalhBZ05jeGpxZFVHaUhKWC9Fb3c4NlROV1dYbnZyOUwya01WcEwxdXphcGlRY3YvWVZ1OFBZZ1ZkU3FGQmlxZG8yNHNMQi9GWFhmMDdSQXJBZ0RLWnZPOFp1YVkiLCJtYWMiOiIyMjI3MjQxOTA5ZGYzOGY0YzQxYjY1NzM1NzAwMzJkYjg1NGNkMjEzOGVkMzk4ZGI0ZmFkNzUyNDk2Y2VkMGU4IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkhJMnljM2ZVdFZ3VVNidFZ4ZDFYUlE9PSIsInZhbHVlIjoia2VhanhrNXFLM2VGQmJhQXJqRGtuV3d0TG1KUGNKS3liT3lkalhBZ05jeGpxZFVHaUhKWC9Fb3c" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im93VCttRE96dzV1UE9FeWZXZWczeFE9PSIsInZhbHVlIjoiUlN1SERaM0ZWVmdrOW1ZZ2dJMkVKMVpHdkZKZmRqTXdLYzBBQVlaNjBSYmNHNTlBdjhtY3VZeHBITlprVnJoTkZmR3lSV2w3WVFvNjJmcHUwR2wrcklXeGNiT1k5RWpLQU5JOG5JUWM1V3dya3lSRkV3b0ZQeTJHdmw5UkpnMFciLCJtYWMiOiI3NDZjOWQyNWQ1ZjVjNzI1ZGIxZTIyMDlkYTAwNzhkMzE3MzdjMDczNWY1ZGY4MjNlZjEzMmViNGE4ZDk2ZWQ3IiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 14:56:08 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Im93VCttRE96dzV1UE9FeWZXZWczeFE9PSIsInZhbHVlIjoiUlN1SERaM0ZWVmdrOW1ZZ2dJMkVKMVpHdkZKZmRqTXdLYzBBQVlaNjBSYmNHNTlBdjhtY3VZeHBITlprVnJoTkZmR3lSV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkhJMnljM2ZVdFZ3VVNidFZ4ZDFYUlE9PSIsInZhbHVlIjoia2VhanhrNXFLM2VGQmJhQXJqRGtuV3d0TG1KUGNKS3liT3lkalhBZ05jeGpxZFVHaUhKWC9Fb3c4NlROV1dYbnZyOUwya01WcEwxdXphcGlRY3YvWVZ1OFBZZ1ZkU3FGQmlxZG8yNHNMQi9GWFhmMDdSQXJBZ0RLWnZPOFp1YVkiLCJtYWMiOiIyMjI3MjQxOTA5ZGYzOGY0YzQxYjY1NzM1NzAwMzJkYjg1NGNkMjEzOGVkMzk4ZGI0ZmFkNzUyNDk2Y2VkMGU4IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkhJMnljM2ZVdFZ3VVNidFZ4ZDFYUlE9PSIsInZhbHVlIjoia2VhanhrNXFLM2VGQmJhQXJqRGtuV3d0TG1KUGNKS3liT3lkalhBZ05jeGpxZFVHaUhKWC9Fb3c" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "izVem1Aa2rr5CNnKzqM48GkCXDYkweLtteG9JNc6" "uc_cart_id" => "f26464b8d6e7158187e2d4764f30f16d" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/106647/cn" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 02:56:08GET/article/106647/cn414413