Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

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

Review Article

Naturally Occurring Steroidal Saponins as Potential Anticancer Agents: Current Developments and Mechanisms of Action

Author(s): Yulin Zou*

Volume 22, Issue 17, 2022

Published on: 20 May, 2022

Page: [1442 - 1456] Pages: 15

DOI: 10.2174/1568026622666220330011047

Price: $65

Abstract

Cancer is claimed as a prevalent cause of mortality throughout the world. Conventional chemotherapy plays a pivotal role in the treatment of cancers, but multidrug resistance has already become one of the major impediments to efficacious cancer therapy, creating a great demand for the development of novel anticancer drugs. Steroidal saponins, abundantly found in nature, possess extensive structural variability, and some naturally occurring steroidal saponins exhibit profound anticancer properties through a variety of pathways. Hence, naturally occurring steroidal saponins are powerful lead compounds/candidates in the development of novel therapeutic agents. This review article described the recent progress of naturally occurring steroidal saponins as potential anticancer agents, and the mechanisms of action were also discussed, covering articles published between 2017 and 2021.

Keywords: Saponins, Steroidal, Natural products, Anticancer activity, Mechanisms of action, Chemotherapy, Multidrug resistance.

« Previous
Graphical Abstract

[1]
Chi, Y.; Wang, D.; Wang, J.; Yu, W.; Yang, J. Long non-coding RNA in the pathogenesis of cancers. Cells, 2019, 8(9), e1015.
[http://dx.doi.org/10.3390/cells8091015 ] [PMID: 31480503]
[2]
Ganesh, K.; Massagué, J. Targeting metastatic cancer. Nat. Med., 2021, 27(1), 34-44.
[http://dx.doi.org/10.1038/s41591-020-01195-4 ] [PMID: 33442008]
[3]
Liu, Y.Q.; Wang, X.L.; He, D.H.; Cheng, Y.X. Protection against chemotherapy- and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals. Phytomedicine, 2021, 80, 153402.
[http://dx.doi.org/10.1016/j.phymed.2020.153402 ] [PMID: 33203590]
[4]
Turanli, B.; Altay, O.; Borén, J.; Turkez, H.; Nielsen, J.; Uhlen, M.; Arga, K.Y.; Mardinoglu, A. Systems biology based drug repositioning for development of cancer therapy. Semin. Cancer Biol., 2021, 68, 47-58.
[http://dx.doi.org/10.1016/j.semcancer.2019.09.020 ] [PMID: 31568815]
[5]
Zhang, H.; Xu, H.; Ashby, C.R., Jr; Assaraf, Y.G.; Chen, Z.S.; Liu, H.M. Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp). Med. Res. Rev., 2021, 41(1), 525-555.
[http://dx.doi.org/10.1002/med.21739 ] [PMID: 33047304]
[6]
Dallavalle, S.; Dobričić, V.; Lazzarato, L.; Gazzano, E.; Machuqueiro, M.; Pajeva, I.; Tsakovska, I.; Zidar, N.; Fruttero, R. Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors. Drug Resist. Updat., 2020, 50, 100682.
[http://dx.doi.org/10.1016/j.drup.2020.100682 ] [PMID: 32087558]
[7]
Sauter, E.R. Cancer prevention and treatment using combination therapy with natural compounds. Expert Rev. Clin. Pharmacol., 2020, 13(3), 265-285.
[http://dx.doi.org/10.1080/17512433.2020.1738218 ] [PMID: 32154753]
[8]
Dutta, S.; Mahalanobish, S.; Saha, S.; Ghosh, S.; Sil, P.C. Natural products: An upcoming therapeutic approach to cancer. Food Chem. Toxicol., 2019, 128, 240-255.
[http://dx.doi.org/10.1016/j.fct.2019.04.012 ] [PMID: 30991130]
[9]
Thu, Z.M.; Oo, S.M.; Nwe, T.M.; Aung, H.T.; Armijos, C.; Hussain, F.H.S.; Vidari, G. Structures and bioactivities of steroidal saponins isolated from the Genera Dracaena and Sansevieria. Molecules, 2021, 26(7), e1916.
[http://dx.doi.org/10.3390/molecules26071916 ] [PMID: 33805482]
[10]
Sobolewska, D.; Galanty, A.; Grabowska, K.; Makowska-Wąs, J.; Wróbel-Biedrawa, D.; Podolak, I. Saponins as cytotoxic agents: An update (2010-2018). Part I-Steroidal saponins. Phytochem. Rev., 2020, 19(1), 139-189.
[http://dx.doi.org/10.1007/s11101-020-09661-0]
[11]
Zhang, Y.W.; Zhao, Y.F.; Wang, Y.R.; Shang, T.T.; Yang, L.M.; Huang, X.F. Steroidal saponins with cytotoxic activities from the rhi-zomes of Anemarrhena asphodeloids Bunge. Phytochem. Lett., 2017, 20, 102-105.
[http://dx.doi.org/10.1016/j.phytol.2017.04.013]
[12]
Liu, J.; Deng, X.; Sun, X.; Dong, J.; Huang, J. Inhibition of autophagy enhances timosaponin AIII-induced lung cancer cell apoptosis and anti-tumor effect in vitro and in vivo. Life Sci., 2020, 257, 118040.
[http://dx.doi.org/10.1016/j.lfs.2020.118040 ] [PMID: 32622943]
[13]
Song, X.Y.; Han, F.Y.; Chen, J.J.; Wang, W.; Zhang, Y.; Yao, G.D.; Song, S.J. Timosaponin AIII, a steroidal saponin, exhibits anti-tumor effect on taxol-resistant cells in vitro and in vivo. Steroids, 2019, 146, 57-64.
[http://dx.doi.org/10.1016/j.steroids.2019.03.009 ] [PMID: 30951756]
[14]
MarElia, C.B.; Sharp, A.E.; Shemwell, T.A.; Clare Zhang, Y.; Burkhardt, B.R. Anemarrhena asphodeloides Bunge and its constituent timosaponin-AIII induce cell cycle arrest and apoptosis in pancreatic cancer cells. FEBS Open Bio, 2018, 8(7), 1155-1166.
[http://dx.doi.org/10.1002/2211-5463.12457 ] [PMID: 29988574]
[15]
Chiang, K.C.; Lai, C.Y.; Chiou, H.L.; Lin, C.L.; Chen, Y.S.; Kao, S.H.; Hsieh, Y.H. Timosaponin AIII inhibits metastasis of renal carci-noma cells through suppressing cathepsin C expression by AKT/miR-129-5p axis. J. Cell. Physiol., 2019, 234(8), 13332-13341.
[http://dx.doi.org/10.1002/jcp.28010 ] [PMID: 30604866]
[16]
Kim, Y.; Kim, K.H.; Lee, I.S.; Park, J.Y.; Na, Y.C.; Chung, W.S.; Jang, H.J. Apoptosis and G2/M cell cycle arrest induced by a timosapo-nin A3 from Anemarrhena asphodeloides Bunge on AsPC-1 pancreatic cancer cells. Phytomedicine, 2019, 56, 48-56.
[http://dx.doi.org/10.1016/j.phymed.2018.08.006 ] [PMID: 30668353]
[17]
Zhou, Z.Y.; Zhao, W.R.; Xiao, Y.; Zhou, X.M.; Huang, C.; Shi, W.T.; Zhang, J.; Ye, Q.; Chen, X.L.; Tang, J.Y. Antiangiogenesis effect of timosaponin AIII on HUVECs in vitro and zebrafish embryos in vivo. Acta Pharmacol. Sin., 2020, 41(2), 260-269.
[http://dx.doi.org/10.1038/s41401-019-0291-z ] [PMID: 31515528]
[18]
Zhang, M.; Qu, J.; Gao, Z.; Qi, Q.; Yin, H.; Zhu, L.; Wu, Y.; Liu, W.; Yang, J.; Huang, X. Timosaponin AIII induces G2/M arrest and apoptosis in breast cancer by activating the ATM/Chk2 and p38 MAPK signaling pathways. Front. Pharmacol., 2021, 11, 601468.
[http://dx.doi.org/10.3389/fphar.2020.601468 ] [PMID: 33628174]
[19]
Gergely, J.E.; Dorsey, A.E.; Dimri, G.P.; Dimri, M. Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein BMI1 in breast cancer cells. Mol. Carcinog., 2018, 57(7), 831-841.
[http://dx.doi.org/10.1002/mc.22804 ] [PMID: 29528145]
[20]
Jung, O.; Lee, S.Y. Synergistic anticancer effects of timosaponin AIII and ginsenosides in MG63 human osteosarcoma cells. J. Ginseng Res., 2019, 43(3), 488-495.
[http://dx.doi.org/10.1016/j.jgr.2018.11.002 ] [PMID: 31308821]
[21]
Lee, S.Y. Ginsenoside Rg1 drives stimulations of timosaponin AIII-induced anticancer effects in human osteosarcoma cells. Evid. Based Complement. Alternat. Med., 2020, 2020, 8980124.
[http://dx.doi.org/10.1155/2020/8980124 ] [PMID: 32774433]
[22]
Teng, J.F.; Qin, D.L.; Mei, Q.B.; Qiu, W.Q.; Pan, R.; Xiong, R.; Zhao, Y.; Law, B.Y.; Wong, V.K.; Tang, Y.; Yu, C.L.; Zhang, F.; Wu, J.M.; Wu, A.G. Polyphyllin VI, a saponin from Trillium tschonoskii Maxim. induces apoptotic and autophagic cell death via the ROS trig-gered mTOR signaling pathway in non-small cell lung cancer. Pharmacol. Res., 2019, 147, 104396.
[http://dx.doi.org/10.1016/j.phrs.2019.104396 ] [PMID: 31404628]
[23]
Teng, J.F.; Mei, Q.B.; Zhou, X.G.; Tang, Y.; Xiong, R.; Qiu, W.Q.; Pan, R.; Law, B.Y.; Wong, V.K.; Yu, C.L.; Long, H.A.; Xiao, X.L.; Zhang, F.; Wu, J.M.; Qin, D.L.; Wu, A.G. Polyphyllin VI induces caspase-1-mediated pyroptosis via the induction of ROS/NF-κB/NLRP3/GSDMD signal axis in non-small cell lung cancer. Cancers (Basel), 2020, 12(1), e193.
[http://dx.doi.org/10.3390/cancers12010193 ] [PMID: 31941010]
[24]
Qin, X.J.; Zhang, L.J.; Zhang, Y.; Ni, W.; Yang, X.Z.; Yu, Q.; Yan, H.; An, L.K.; Liu, H.Y. Polyphyllosides A-F, six new spirostanol saponins from the stems and leaves of Paris polyphylla var. chinensis. Bioorg. Chem., 2020, 99, 103788.
[http://dx.doi.org/10.1016/j.bioorg.2020.103788 ] [PMID: 32244126]
[25]
Zhang, F.; Zhang, Y.Y.; Sun, Y.S.; Ma, R.H.; Thakur, K.; Zhang, J.G.; Wei, Z.J. Asparanin A from Asparagus of ficinalis L. induces G0/G1 cell cycle arrest and apoptosis in human endometrial carcinoma Ishikawa cells via mitochondrial and PI3K/AKT signaling path-ways. J. Agric. Food Chem., 2020, 68(1), 213-224.
[http://dx.doi.org/10.1021/acs.jafc.9b07103 ] [PMID: 31861958]
[26]
Xiang, W.; Zhang, R.J.; Jin, G.L.; Tian, L.; Cheng, F.; Wang, J.Z.; Xing, X.F.; Xi, W.; Tang, S.J.; Chen, J.F. RCE 4, a potential anti cervical cancer drug isolated from Reineckia carnea, induces autophagy via the dual blockade of PI3K and ERK pathways in cervical cancer CaSki cells. Int. J. Mol. Med., 2020, 45(1), 245-254.
[PMID: 31746346]
[27]
You, F.F.; Zhang, J.; Cheng, F.; Zou, K.; Zhang, X.Q.; Chen, J.F. ATG 4B serves a crucial role in rce-4-induced inhibition of the bcl-2-beclin 1 complex in cervical cancer caski cells. Int. J. Mol. Sci., 2021, 22(22), e12302.
[http://dx.doi.org/10.3390/ijms222212302 ] [PMID: 34830185]
[28]
Mbaveng, A.T.; Chi, G.F.; Nguenang, G.S.; Abdelfatah, S.; Tchangna Sop, R.V.; Ngadjui, B.T.; Kuete, V.; Efferth, T. Cytotoxicity of a naturally occuring spirostanol saponin, progenin III, towards a broad range of cancer cell lines by induction of apoptosis, autophagy and necroptosis. Chem. Biol. Interact., 2020, 326, 109141.
[http://dx.doi.org/10.1016/j.cbi.2020.109141 ] [PMID: 32454006]
[29]
Yang, Y.J.; Pang, X.; Wang, B.; Yang, J.; Chen, X.J.; Sun, X.G.; Li, Q.; Zhang, J.; Guo, B.L.; Ma, B.P. Steroidal saponins from Trillium tschonoskii rhizomes and their cytotoxicity against HepG2 cells. Steroids, 2020, 156, 108587.
[http://dx.doi.org/10.1016/j.steroids.2020.108587 ] [PMID: 31982423]
[30]
Kaunda, J.S.; Zhang, Y.J. Two new 23S,26R-hydroxylated spirostanoid saponins from the fruits of Solanum indicum var. recurvatum. Steroids, 2020, 153, 108506.
[http://dx.doi.org/10.1016/j.steroids.2019.108506 ] [PMID: 31586607]
[31]
Yu, H.; Wang, H.; Yin, Y.; Wang, Z. Liriopesides B from Liriope spicata var. prolifera inhibits metastasis and induces apoptosis in A2780 human ovarian cancer cells. Mol. Med. Rep., 2020, 22(3), 1747-1758.
[http://dx.doi.org/10.3892/mmr.2020.11256 ] [PMID: 32582970]
[32]
Yuan, S.; Xu, Y.; Yi, T.; Wang, H. The anti-tumor effect of OP-B on ovarian cancer in vitro and in vivo, and its mechanism: An investiga-tion using network pharmacology-based analysis. J. Ethnopharmacol., 2022, 283, 114706.
[33]
Gao, G.Y.; Ma, J.; Lu, P.; Jiang, X.; Chang, C. Ophiopogonin B induces the autophagy and apoptosis of colon cancer cells by activating JNK/c-Jun signaling pathway. Biomed. Pharmacother., 2018, 108, 1208-1215.
[http://dx.doi.org/10.1016/j.biopha.2018.06.172 ] [PMID: 30372822]
[34]
Chen, M.; Hu, C.; Guo, Y.; Jiang, R.; Jiang, H.; Zhou, Y.; Fu, H.; Wu, M.; Zhang, X. Ophiopogonin B suppresses the metastasis and an-giogenesis of A549 cells in vitro and in vivo by inhibiting the EphA2/Akt signaling pathway. Oncol. Rep., 2018, 40(3), 1339-1347.
[http://dx.doi.org/10.3892/or.2018.6531 ] [PMID: 29956803]
[35]
Zhang, S.; Li, H.; Li, L.; Gao, Q.; Gu, L.; Hu, C.; Chen, M.; Zhang, X. Ophiopogonin B inhibits migration and invasion in non-small cell lung cancer cells through enhancing the interaction between Axin and β-catenin. J. Cancer, 2021, 12(20), 6274-6284.
[http://dx.doi.org/10.7150/jca.60066 ] [PMID: 34539900]
[36]
Dong, W.H.; Dong, Q.; Ding, H.R. Ophiopogonin B induces reactive oxygen species-dependent apoptosis through the Hippo pathway in nasopharyngeal carcinoma. Mol. Med. Rep., 2021, 24(1), e12173.
[http://dx.doi.org/10.3892/mmr.2021.12173]
[37]
Hu, C.; Jiang, R.; Cheng, Z.; Lu, Y.; Gu, L.; Li, H.; Li, L.; Gao, Q.; Chen, M.; Zhang, X. Ophiopogonin-B suppresses epithelial-mesenchymal transition in human lung adenocarcinoma cells via the Linc00668/miR-432-5p/EMT axis. J. Cancer, 2019, 10(13), 2849-2856.
[http://dx.doi.org/10.7150/jca.31338 ] [PMID: 31281461]
[38]
He, B.; Zhou, X.; Shi, D.; Cheng, G. Progress on anti-tumor effects and mechanisms of ophiopogonin B. Zhonghua Zhongyiyao Xuekan, 2018, 36, 2911-2914.
[39]
Cuong, L.C.; Nhi, N.P.K.; Ha, T.P.; Anh, L.T.; Dat, T.T.H.; Oanh, P.T.T.; Phuong, N.T.M.; Thu, V.T.K.; Duc, H.V.; Anh, H.L.T. A new steroidal saponin from the aerial parts of Solanum torvum Viet. Nat. Prod. Res., 2022, 1-6.
[http://dx.doi.org/10.1080/14786419.2021.1908282]
[40]
Wu, A.G.; Teng, J.F.; Wong, V.K.W.; Zhou, X.G.; Qiu, W.Q.; Tang, Y.; Wu, J.M.; Xiong, R.; Pan, R.; Wang, Y.L.; Tang, B.; Ding, T.Y.; Yu, L.; Zeng, W.; Qin, D.L.; Law, B.Y. Novel steroidal saponin isolated from Trillium tschonoskii maxim. exhibits anti-oxidative effect via autophagy induction in cellular and Caenorhabditis elegans models. Phytomedicine, 2019, 65, 153088.
[http://dx.doi.org/10.1016/j.phymed.2019.153088 ] [PMID: 31627105]
[41]
Dai, Z.; Liu, H.; Wang, B.; Yang, D.; Zhu, Y.Y.; Yan, H.; Zhu, P.F.; Liu, Y.P.; Chen, H.C.; Zhao, Y.L.; Zhao, L.X.; Zhao, X.D.; Liu, H.Y.; Luo, X.D. Structures/cytotoxicity/selectivity relationship of natural steroidal saponins against GSCs and primary mechanism of tribulosaponin A. Eur. J. Med. Chem., 2021, 210, 113068.
[http://dx.doi.org/10.1016/j.ejmech.2020.113068 ] [PMID: 33310292]
[42]
Tian, Y.; Gong, G.Y.; Ma, L.L.; Wang, Z.Q.; Song, D.; Fang, M.Y. Anti-cancer effects of Polyphyllin I: An update in 5 years. Chem.-. Biol. Int., 2020, 316, 108936.
[43]
Liu, M.M.; Zhu, M.L.; Dong, R.F.; Zhang, C.; Zhang, H.; Yang, L.; Kong, L.Y.; Xia, Y.Z. Polyphyllin I promotes cell death via suppress-ing UPR-mediated CHOP ubiquitination and degradation in non-small cell lung cancer. Chin. J. Nat. Med., 2021, 19(4), 255-266.
[http://dx.doi.org/10.1016/S1875-5364(21)60027-4 ] [PMID: 33875166]
[44]
Shen, Z.; Wang, J.; Ke, K.; Chen, R.; Zuo, A.; Zhang, R.; Wan, W.; Xie, X.; Li, X.; Song, N.; Fu, H.; Zhang, Z.; Cai, E.; Shen, J.; Zhang, Q.; Shi, X. Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb path-way in vitro and in vivo. Cell Cycle, 2021, 20(23), 2494-2506.
[http://dx.doi.org/10.1080/15384101.2021.1991121 ] [PMID: 34658297]
[45]
Yu, S.; Wang, L.; Cao, Z.; Gong, D.; Liang, Q.; Chen, H.; Fu, H.; Wang, W.; Tang, X.; Xie, Z.; He, Y.; Peng, C.; Li, Y. Anticancer effect of Polyphyllin I in colorectal cancer cells through ROS-dependent autophagy and G2/M arrest mechanisms. Nat. Prod. Res., 2018, 32(12), 1489-1492.
[http://dx.doi.org/10.1080/14786419.2017.1353512 ] [PMID: 28714320]
[46]
Li, H.S.; Xu, Y. Inhibition of EZH2 via the STAT3/HOTAIR signalling axis contributes to cell cycle arrest and apoptosis induced by polyphyllin I in human non-small cell lung cancer cells. Steroids, 2020, 164, 108729.
[http://dx.doi.org/10.1016/j.steroids.2020.108729 ] [PMID: 32941921]
[47]
Han, J.; Kan, J.; Wang, X.; Yuan, Q.; Song, X.; Huang, M.; Wu, H. Polyphyllin I suppresses proliferation and promotes apoptosis of gastric cancer cell by inhibiting stat3 phosphorylation. Transl. Cancer Res., 2020, 9(8), 4715-4725.
[http://dx.doi.org/10.21037/tcr-20-66 ] [PMID: 35117835]
[48]
Yang, Q.; Chen, W.; Xu, Y.; Lv, X.; Zhang, M.; Jiang, H. Polyphyllin I modulates MALAT1/STAT3 signaling to induce apoptosis in gefitinib-resistant non-small cell lung cancer. Toxicol. Appl. Pharmacol., 2018, 356, 1-7.
[http://dx.doi.org/10.1016/j.taap.2018.07.031 ] [PMID: 30076870]
[49]
Lai, L.; Shen, Q.; Wang, Y.; Chen, L.; Lai, J.; Wu, Z.; Jiang, H. Polyphyllin I reverses the resistance of osimertinib in non-small cell lung cancer cell through regulation of PI3K/Akt signaling. Toxicol. Appl. Pharmacol., 2021, 419, 115518.
[http://dx.doi.org/10.1016/j.taap.2021.115518 ] [PMID: 33812963]
[50]
Pang, D.; Yang, C.; Li, C.; Zou, Y.; Feng, B.; Li, L.; Liu, W.; Luo, Q.; Chen, Z.; Huang, C. Polyphyllin II inhibits liver cancer cell prolif-eration, migration and invasion through downregulated cofilin activity and the AKT/NF-κB pathway. Biol. Open, 2020, 9(2), BIO046854.
[http://dx.doi.org/10.1242/bio.046854 ] [PMID: 31988091]
[51]
Wang, W.; Dong, X.; You, L.; Sai, N.; Leng, X.; Yang, C.; Yin, X.; Ni, J. Apoptosis in HepaRG and HL-7702 cells inducted by polyphyl-lin II through caspases activation and cell-cycle arrest. J. Cell. Physiol., 2019, 234(5), 7078-7089.
[http://dx.doi.org/10.1002/jcp.27462 ] [PMID: 30362578]
[52]
Zhou, Y.; Yang, J.; Chen, C.; Li, Z.; Chen, Y.; Zhang, X.; Wang, L.; Zhou, J. Polyphyllin III-induced ferroptosis in MDA-MB-231 triple-negative breast cancer cells can be protected against by KLF4-mediated upregulation of xCT. Front. Pharmacol., 2021, 12, e670224.
[http://dx.doi.org/10.3389/fphar.2021.670224]
[53]
Wang, Y.H.; Shi, M.; Niu, H.M.; Yang, J.; Xia, M.Y.; Luo, J.F.; Chen, Y.J.; Zhou, Y.P.; Li, H. Substituting one Paris for another? In vitro cytotoxic and in vivo antitumor activities of Paris forrestii, a substitute of Paris polyphylla var. yunnanensis. J. Ethnopharmacol., 2018, 218, 45-50.
[http://dx.doi.org/10.1016/j.jep.2018.02.022 ] [PMID: 29454914]
[54]
Zheng, B.; Wang, G.; Gao, W.; Wu, Q.; Zhu, W.; Weng, G. SOX7 is involved in polyphyllin D-induced G0/G1 cell cycle arrest through down-regulation of cyclin D1. Acta Pharm., 2020, 70(2), 191-200.
[http://dx.doi.org/10.2478/acph-2020-0017 ] [PMID: 31955140]
[55]
Liu, J.; Liu, Y.; Li, H.; Wei, C.; Mao, A.; Liu, W.; Pan, G. Polyphyllin D induces apoptosis and protective autophagy in breast cancer cells through JNK1-Bcl-2 pathway. J. Ethnopharmacol., 2022, 282, 114591.
[http://dx.doi.org/10.1016/j.jep.2021.114591 ] [PMID: 34481873]
[56]
Zhang, S.; Lu, Y.; Li, H.; Ji, Y.; Fang, F.; Tang, H.; Qiu, P.; Qiu, P. A steroidal saponin form Paris vietnamensis (Takht.) reverses te-mozolomide resistance in glioblastoma cells via inducing apoptosis through ROS/PI3K/Akt pathway. Biosci. Trends, 2020, 14(2), 123-133.
[http://dx.doi.org/10.5582/bst.2020.01005 ] [PMID: 32173672]
[57]
Yang, J.; Cao, L.; Li, Y.; Liu, H.; Zhang, M.; Ma, H.; Wang, B.; Yuan, X.; Liu, Q. Gracillin isolated from Reineckia carnea induces apop-tosis of A549 cells via the mitochondrial pathway. Drug Des. Devel. Ther., 2021, 15, 233-243.
[http://dx.doi.org/10.2147/DDDT.S278975 ] [PMID: 33505158]
[58]
Chen, J.; Fan, Y.; Lin, M.; Lin, X.; Lin, Z.; Liu, We.; Wang, Y. Beneficial effects of gracillin rrom Rhizoma paridis against gastric carci-noma via the potential TIPE2-mediated induction of endogenous apoptosis and inhibition of migration in BGC823 cells. Front. Pharmacol., 2021, 12, e669199.
[59]
Yang, L.; Zhu, T.; Ye, H.; Shen, Y.; Li, Z.; Chen, L.; Wang, C.; Chen, X.; Zhao, H.; Xiang, Y.; Xiao, Z.; Zhao, C.; Li, J.; Hu, W. Gracillin shows potent efficacy against colorectal cancer through inhibiting the STAT3 pathway. J. Cell. Mol. Med., 2021, 25(2), 801-812.
[http://dx.doi.org/10.1111/jcmm.16134 ] [PMID: 33259114]
[60]
Min, H.Y.; Pei, H.; Hyun, S.Y.; Boo, H.J.; Jang, H.J.; Cho, J.; Kim, J.H.; Son, J.; Lee, H.Y. Potent anticancer effect of the natural steroidal saponin gracillin is produced by inhibiting glycolysis and oxidative phosphorylation-mediated bioenergetics. Cancers (Basel), 2020, 12(4), e913.
[http://dx.doi.org/10.3390/cancers12040913 ] [PMID: 32276500]
[61]
Chen, G.; Xie, Y. Dioscin induces ferroptosis and synergistic cytotoxicity with chemotherapeutics in melanoma cells. Biochem. Biophys. Res. Commun., 2021, 557, 213-220.
[62]
Wang, P.; Wang, C.; Liu, C. Antitumor effects of dioscin in A431 cells via adjusting ATM/p53-mediated cell apoptosis, DNA damage and migration. Oncol. Lett., 2021, 21(1), 59.
[http://dx.doi.org/10.3892/ol.2020.12321 ] [PMID: 33281970]
[63]
Cui, L.; Yang, G.; Ye, J.; Yao, Y.; Lu, G.; Chen, J.; Fang, L.; Lu, S.; Zhou, J. Dioscin elicits anti-tumour immunity by inhibiting macro-phage M2 polarization via JNK and STAT3 pathways in lung cancer. J. Cell. Mol. Med., 2020, 24(16), 9217-9230.
[http://dx.doi.org/10.1111/jcmm.15563 ] [PMID: 32618105]
[64]
Ding, Q.; Zhang, W.; Cheng, C.; Mo, F.; Chen, L.; Peng, G.; Cai, X.; Wang, J.; Yang, S.; Liu, X. Dioscin inhibits the growth of human osteosarcoma by inducing G2/M-phase arrest, apoptosis, and GSDME-dependent cell death in vitro and in vivo. J. Cell. Physiol., 2020, 235(3), 2911-2924.
[http://dx.doi.org/10.1002/jcp.29197 ] [PMID: 31535374]
[65]
Okubo, S.; Ohta, T.; Shoyama, Y.; Uto, T. Steroidal saponins isolated from the rhizome of dioscorea tokoro inhibit cell growth and au-tophagy in hepatocellular carcinoma cells. Life (Basel), 2021, 11(8), e749.
[http://dx.doi.org/10.3390/life11080749 ] [PMID: 34440493]
[66]
Li, X.L.; Ma, R.H.; Ni, Z.J.; Thakur, K.; Cespedes-Acuña, C.L.; Wang, S.; Zhang, J.G.; Wei, Z.J. Dioscin inhibits human endometrial carcinoma proliferation via G0/G1 cell cycle arrest and mitochondrial-dependent signaling pathway. Food Chem. Toxicol., 2021, 148, 111941.
[http://dx.doi.org/10.1016/j.fct.2020.111941 ] [PMID: 33359023]
[67]
Wu, Z.; Han, X.; Tan, G.; Zhu, Q.; Chen, H.; Xia, Y.; Gong, J.; Wang, Z.; Wang, Y.; Yan, J. Dioscin inhibited glycolysis and induced cell apoptosis in colorectal cancer via promoting c-myc ubiquitination and subsequent hexokinase-2 suppression. OncoTargets Ther., 2020, 13, 31-44.
[http://dx.doi.org/10.2147/OTT.S224062 ] [PMID: 32021252]
[68]
Li, S.; Cheng, B.; Hou, L.; Huang, L.; Cui, Y.; Xu, D.; Shen, X.; Li, S. Dioscin inhibits colon cancer cells’ growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways. Anticancer Drugs, 2018, 29(3), 234-242.
[http://dx.doi.org/10.1097/CAD.0000000000000590 ] [PMID: 29389802]
[69]
Guo, X.; Ding, X. Dioscin suppresses the viability of ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways. Oncol. Lett., 2018, 15(6), 9537-9542.
[http://dx.doi.org/10.3892/ol.2018.8454 ] [PMID: 29805675]
[70]
Li, X.; Qu, Z.; Jing, S.; Li, X.; Zhao, C.; Man, S.; Wang, Y.; Gao, W. Dioscin-6′-O-acetate inhibits lung cancer cell proliferation via induc-ing cell cycle arrest and caspase-dependent apoptosis. Phytomedicine, 2019, 53, 124-133.
[http://dx.doi.org/10.1016/j.phymed.2018.09.033 ] [PMID: 30668391]
[71]
Li, X.; Sun, J.; Li, X.; Dai, Y.; Zhao, C.; Man, S.; Wang, Y.; Gao, W. Dioscin-6′-O-acetate impairs migration of lung cancer cells through attenuations of MMP-2 and MMP-9 via NF-κB suppression. Med. Chem. Res., 2019, 28(1), 1-12.
[http://dx.doi.org/10.1007/s00044-018-2257-y]
[72]
Ho, D.V.; Hoang, H.N.T.; Vo, H.Q.; Nguyen, K.V.; Pham, T.V.; Le, A.T.; Van Phan, K.; Nguyen, H.M.; Morita, H.; Nguyen, H.T. Three new steroidal saponins from Aspidistra letreae plants and their cytotoxic activities. J. Nat. Med., 2020, 74(3), 591-598.
[http://dx.doi.org/10.1007/s11418-020-01395-9 ] [PMID: 32200514]
[73]
Nguyen, H.M.; Nguyen, H.T.; Seephan, S.; Do, H.B.; Nguyen, H.T.; Ho, D.V.; Pongrakhananon, V. Antitumor activities of Aspiletrein A, a steroidal saponin from Aspidistra letreae, on non-small cell lung cancer cells. BMC Complement. Med. Ther., 2021, 21(1), 87.
[http://dx.doi.org/10.1186/s12906-021-03262-w ] [PMID: 33750378]
[74]
Zhang, Y.; Zhao, Y.; Wu, Y.; Qi, J.; Li, F.; Kou, J.; Yu, B. Ophiopogon saponin c1 inhibits lung tumors by stabilizing endothelium per-meability via inhibition of PKCδ. Int. J. Biol. Sci., 2020, 16(3), 396-407.
[http://dx.doi.org/10.7150/ijbs.34978 ] [PMID: 32015677]
[75]
Wei, X.; Mao, T.; Li, S.; He, J.; Hou, X.; Li, H.; Zhan, M.; Yang, X.; Li, R.; Xiao, J.; Yuan, S.; Sun, L. DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway. Phytomedicine, 2019, 54, 120-131.
[http://dx.doi.org/10.1016/j.phymed.2018.09.003 ] [PMID: 30668361]
[76]
Wang, Z.; Wang, Y.; Zhu, S.; Liu, Y.; Peng, X.; Zhang, S.; Zhang, Z.; Qiu, Y.; Jin, M.; Wang, R.; Zhong, Y.; Kong, D. DT-13 inhibits proliferation and metastasis of human prostate cancer cells through blocking PI3K/Akt pathway. Front. Pharmacol., 2018, 9, 1450.
[http://dx.doi.org/10.3389/fphar.2018.01450 ] [PMID: 30581390]
[77]
Xu, J.; Wang, Z.; Huang, Y.; Wang, Y.; Xiang, L.; He, X. A spirostanol saponin isolated from Tupistra chinensis Baker simultaneously induces apoptosis and autophagy by regulating the JNK pathway in human gastric cancer cells. Steroids, 2020, 164, 108737.
[http://dx.doi.org/10.1016/j.steroids.2020.108737 ] [PMID: 33002483]
[78]
Xu, J.; Wang, Y.; Wang, Z.; Wang, Y.; He, X. T-17, a spirostanol saponin, inhibits p53-independent proliferation and p53-dependent migration of gastric cancer cells. Steroids, 2021, 170, 108828.
[http://dx.doi.org/10.1016/j.steroids.2021.108828 ] [PMID: 33781788]
[79]
Yang, C.; Lin, W.; Zhao, L.; Cai, J. A new furostanol saponin from Dendrobium chrysanthum Lindl. with cytotoxic activity. Nat. Prod. Res., 2019, 33(17), 2461-2465.
[http://dx.doi.org/10.1080/14786419.2018.1452007 ] [PMID: 29577750]
[80]
Tai, B.H.; Doan, V.V.; Yen, P.H.; Nhiem, N.X.; Cuc, N.T.; Trang, D.T.; Hang, D.T.T.; Van Minh, C.; Van Kiem, P. Two new steroidal alkaloid saponins from the whole plants of Solanum nigrum. Nat. Prod. Commun., 2018, 13(11), 1457-1460.
[http://dx.doi.org/10.1177/1934578X1801301111]
[81]
Man, S.; Lv, P.; Cui, J.; Liu, F.; Peng, L.; Ma, L.; Liu, C.; Gao, W. Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin. Toxicol. Appl. Pharmacol., 2020, 406, 115206.
[http://dx.doi.org/10.1016/j.taap.2020.115206 ] [PMID: 32835762]
[82]
Chen, M.; Ye, K.; Zhang, B.; Xin, Q.; Li, P.; Kong, A.N.; Wen, X.; Yang, J. Paris Saponin II inhibits colorectal carcinogenesis by regulat-ing mitochondrial fission and NF-κB pathway. Pharmacol. Res., 2019, 139, 273-285.
[http://dx.doi.org/10.1016/j.phrs.2018.11.029 ] [PMID: 30471409]
[83]
Lin, X.; Gajendran, B.; Varier, K.M.; Liu, W.; Song, J.; Rao, Q.; Wang, C.; Qiu, J.; Ni, W.; Qin, X.; Wen, M.; Liu, H.; Li, Y. Paris saponin VII induces apoptosis and cell cycle arrest in erythroleukemia cells by a mitochondrial membrane signaling pathway. Anticancer. Agents Med. Chem., 2021, 21(4), 498-507.
[http://dx.doi.org/10.2174/1871520620666200615134039 ] [PMID: 32538736]
[84]
Tang, G.E.; Niu, Y.X.; Li, Y.; Wu, C.Y.; Wang, X.Y.; Zhang, J. Paris saponin VII enhanced the sensitivity of HepG2/ADR cells to ADR via modulation of PI3K/AKT/MAPK signaling pathway. Kaohsiung J. Med. Sci., 2020, 36(2), 98-106.
[http://dx.doi.org/10.1002/kjm2.12145 ] [PMID: 31688993]
[85]
Xiang, Y.C.; Shen, J.; Si, Y.; Liu, X.W.; Zhang, L.; Wen, J.; Zhang, T.; Yu, Q.Q.; Lu, J.F.; Xiang, K.; Liu, Y. Paris saponin VII, a direct activator of AMPK, induces autophagy and exhibits therapeutic potential in non-small-cell lung cancer. Chin. J. Nat. Med., 2021, 19(3), 195-204.
[http://dx.doi.org/10.1016/S1875-5364(21)60021-3 ] [PMID: 33781453]
[86]
Jin, X.; Liu, X.W.; Liu, Y.; Peng, P.; Ren, Y.L.; Shen, J.; Si, Y.; Zhang, T.; Zhao, H.A. Paris saponin VII, a Hippo pathway activator, induces autophagy and exhibits therapeutic potential against human breast cancer cells. Acta Pharmacol. Sin., 2022. Epub ahead of print
[http://dx.doi.org/10.1038/s41401-021-00755-9]
[87]
Zhang, C.; Li, Q.; Qin, G.; Zhang, Y.; Li, C.; Han, L.; Wang, R.; Wang, S.; Chen, H.; Liu, K.; He, C. Anti-angiogenesis and anti-metastasis effects of Polyphyllin VII on Hepatocellular carcinoma cells in vitro and in vivo. Chin. Med., 2021, 16(1), 41.
[http://dx.doi.org/10.1186/s13020-021-00447-w ] [PMID: 34059099]
[88]
Qian, S.; Tong, S.; Wu, J.; Tian, L.; Qi, Z.; Chen, B.; Zhu, D.; Zhang, Y. Paris saponin VII extracted from Trillium tschonoskii induces autophagy and apoptosis in NSCLC cells. J. Ethnopharmacol., 2020, 248, 112304.
[http://dx.doi.org/10.1016/j.jep.2019.112304 ] [PMID: 31626908]
[89]
Zhou, H.; Sun, Y.; Zheng, H.; Fan, L.; Mei, Q.; Tang, Y.; Duan, X.; Li, Y. Paris saponin VII extracted from trillium tschonoskii suppress-es proliferation and induces apoptosis of human colorectal cancer cells. J. Ethnopharmacol., 2019, 239, 111903.
[http://dx.doi.org/10.1016/j.jep.2019.111903 ] [PMID: 31047966]
[90]
Li, Y.; Sun, Y.; Tang, T.; Niu, Y.; Li, X.; Xie, M.; Jin, H.; Mei, Q. Paris saponin VII reverses chemoresistance in breast MCF-7/ADR cells. J. Ethnopharmacol., 2019, 232, 47-54.
[http://dx.doi.org/10.1016/j.jep.2018.12.018 ] [PMID: 30552993]
[91]
Zhou, J.L.; Huang, X.Y.; Qiu, H.C.; Gan, R.Z.; Zhou, H.; Zhu, H.Q.; Zhang, X.X.; Lu, G.D.; Liang, G. SSPH I, a novel anti-cancer sapo-nin, inhibits autophagy and induces apoptosis via ROS accumulation and ERK1/2 signaling pathway in hepatocellular carcinoma cells. OncoTargets Ther., 2020, 13, 5979-5991.
[http://dx.doi.org/10.2147/OTT.S253234 ] [PMID: 32606806]
[92]
Liu, X.; Zhou, P.; He, K.; Wen, Z.; Gao, Y. Dioscorea zingiberensis new saponin inhibits the growth of hepatocellular carcinoma by sup-pressing the expression of long non-coding RNA TCONS-00026762. Front. Pharmacol., 2021, 12, 678620.
[http://dx.doi.org/10.3389/fphar.2021.678620 ] [PMID: 34012402]
[93]
Xu, J.; Zhang, M.; Lin, X.; Wang, Y.; He, X. A steroidal saponin isolated from Allium chinense simultaneously induces apoptosis and autophagy by modulating the PI3K/Akt/mTOR signaling pathway in human gastric adenocarcinoma. Steroids, 2020, 161, 108672.
[http://dx.doi.org/10.1016/j.steroids.2020.108672 ] [PMID: 32485185]
[94]
Xu, J.; Wang, Y.; Wang, Y.; Wang, Z.; He, X. A-24, a steroidal saponin from Allium chinense, induced apoptosis, autophagy and migra-tion inhibition in p53 wild-type and p53-deficient gastric cancer cells. Chem. Biol. Interact., 2021, 348, 109648.
[http://dx.doi.org/10.1016/j.cbi.2021.109648 ] [PMID: 34506766]
[95]
Chu, H.B.; Li, R.; Gao, Y.; Li, D.; Zhang, J.P.; Dan, Z.L. Cytotoxic steroidal glycosides from the underground parts of Hosta ventricosa. J. Asian Nat. Prod. Res., 2021, 23(9), 825-836.
[http://dx.doi.org/10.1080/10286020.2020.1787995 ] [PMID: 32654516]
[96]
Wang, Y.; Yi, X.; Xiang, L.; Huang, Y.; Wang, Z.; He, X. Furostanol saponins from Chinese onion induce G2/M cell-cycle arrest and apoptosis through mitochondria-mediate pathway in HepG2 cells. Steroids, 2019, 148, 11-18.
[http://dx.doi.org/10.1016/j.steroids.2019.04.003 ] [PMID: 31026467]
[97]
Ma, Y.L.; Zhang, Y.S.; Zhang, F.; Zhang, Y.Y.; Thakur, K.; Zhang, J.G.; Wei, Z.J. Methyl protodioscin from Polygonatum sibiricum inhibits cervical cancer through cell cycle arrest and apoptosis induction. Food Chem. Toxicol., 2019, 132, 110655.
[http://dx.doi.org/10.1016/j.fct.2019.110655 ] [PMID: 31271762]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version492msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[20:47:59] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[20:47:59] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[20:47:59] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[20:47:59] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (147ms)time
  • Application (345ms)time
  • 1 x Application (70.14%)
    345ms
    1 x Booting (29.86%)
    147ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated231ms
    • 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 ('316202228','',1,1740775679,1740775679) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740775679
      1.89msalphaeurekaselec_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 ('316202228','/article/122027',1,1740775679,1740775679)
      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
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) 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 >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) 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 >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) 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 >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) 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 >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) 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 >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316202228 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316202228) limit 1
      18.78msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316202228
      • 1: 316202228
      • 2: 316202228
      • 3: 316202228
      • 4: 316202228
      • 5: 316202228
      • 6: 316202228
      • 7: 316202228
      • 8: 316202228
      • 9: 316202228
      • 10: 316202228
      • 11: 316202228
      • 12: 316202228
      • 13: 316202228
      • 14: 316202228
      • 15: 316202228
      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=122027
      1.28msalphaeurekaselec_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
      1.1msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 38
      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`
      3.33msalphaeurekaselec_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
      1.46msalphaeurekaselec_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`
      4.8msalphaeurekaselec_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
      3.19msalphaeurekaselec_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` = '122027'
      1.98msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 122027
      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` = '122027'
      4.17msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 122027
      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` = '122027' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      11.15msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 122027
      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
      540μsalphaeurekaselec_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
      1.47msalphaeurekaselec_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
      51.51msalphaeurekaselec_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
      42.09msalphaeurekaselec_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
      29.42msalphaeurekaselec_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` = 122027 limit 1
      3.22msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 122027
      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 = 122027 and content_type = 'article' order by status desc limit 1
      370μsalphaeurekaselec_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` = 202807 limit 1
      400μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 202807
      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
      380μsalphaeurekaselec_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
      490μsalphaeurekaselec_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 = '122027' 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 = '11712' 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) )
      460μsalphaeurekaselec_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 = '3201' 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) )
      540μsalphaeurekaselec_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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3201) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3201) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3201)
      33.9msalphaeurekaselec_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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11712) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11712) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11712)
      950μsalphaeurekaselec_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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 122027) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 122027) 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 <= 316202228 and j.to_ip >=316202228 )) and ((j.from_date <= 1740775679 and j.to_date >= 1740775679 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 122027)
      740μsalphaeurekaselec_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` < '1442' and is_uploaded = 1 and issue_id = 11712 order by cast(first_page as SIGNED) desc limit 1
      680μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1442
      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` > '1456' and is_uploaded = 1 and issue_id = 11712 order by cast(first_page as SIGNED) asc limit 1
      780μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1456
      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'
      1.25msalphaeurekaselec_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
      340μsalphaeurekaselec_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` = 122027 limit 1
      3.83msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 122027
      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` <= 1740775679 and `b`.`banner_to_date` >= 1740775679 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.97msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740775679
      • 4: 1740775679
      • 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` <= 1740775679 and `b`.`banner_to_date` >= 1740775679 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.75msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740775679
      • 4: 1740775679
      • 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='dcb918d7f954dbd458ac622181e4bfe5'
      300μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        tzItREzwxTMjvoW9461d7ZSRCwxW4tGpBsKgwURs
        uc_cart_id
        dcb918d7f954dbd458ac622181e4bfe5
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/122027" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/122027
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Fri, 28 Feb 2025 20:47:59 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpOSTZ4V041ejkwbkRudUxBV0FjTFE9PSIsInZhbHVlIjoiUllJK1FJK0JSckcxQ2tZQlRoZGRNRW0veTJiZjNodmlpaHlhQlhYUkNTa3piUmMwdkZOYVZkd1pzM0VoYXVkVDlDT3J1NXh2YjE4Y0dLZGlWT1JyTWVMZUM1TEdMckNXNG54a1h1cGR4S3NFME1VRmdaV3FSZW45R2d4U1pNd0UiLCJtYWMiOiI0NzM0ZWU3OGE5MTIxYjVmMjE3NjU1M2YzMjQyNDhkOGRkNDM4ZjM4YTdkYTFmNWRmODk5ZDg5ZGU4OGY4NmZiIiwidGFnIjoiIn0%3D; expires=Mon, 03 Mar 2025 08:47:59 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImpOSTZ4V041ejkwbkRudUxBV0FjTFE9PSIsInZhbHVlIjoiUllJK1FJK0JSckcxQ2tZQlRoZGRNRW0veTJiZjNodmlpaHlhQlhYUkNTa3piUmMwdkZOYVZkd1pzM0VoYXVkVDlDT3J1N" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkRyazZqcForeU1vV2ttcFhzbzF5Ymc9PSIsInZhbHVlIjoiY0p4clVpTWJJWTdoaEFtRGowSFhZRGEzMHhjejB6MzFSbURlVFNzSXFYSUJxRTd0cnhWTC83T3hVVklCRVFFRUFkWlVyc29tdkxGc0dXOEpvRkVaRm1sN293UitxalVxQmJ3bkRLYWYzanhPNnAxTTN0WEtwN1lPNnRvWTV3ajYiLCJtYWMiOiI0NDU0YzdmODM1MjQxYjQxYjYxNTlkZWQ0ZGIzZmQyOWUwNmFkZTk1YzMzNWI2NTVmYzdlNmIxZWM3ZjEyMzgwIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkRyazZqcForeU1vV2ttcFhzbzF5Ymc9PSIsInZhbHVlIjoiY0p4clVpTWJJWTdoaEFtRGowSFhZRGEzMHhjejB6MzFSbURlVFNzSXFYSUJxRTd0cnhWTC83T3h" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpOSTZ4V041ejkwbkRudUxBV0FjTFE9PSIsInZhbHVlIjoiUllJK1FJK0JSckcxQ2tZQlRoZGRNRW0veTJiZjNodmlpaHlhQlhYUkNTa3piUmMwdkZOYVZkd1pzM0VoYXVkVDlDT3J1NXh2YjE4Y0dLZGlWT1JyTWVMZUM1TEdMckNXNG54a1h1cGR4S3NFME1VRmdaV3FSZW45R2d4U1pNd0UiLCJtYWMiOiI0NzM0ZWU3OGE5MTIxYjVmMjE3NjU1M2YzMjQyNDhkOGRkNDM4ZjM4YTdkYTFmNWRmODk5ZDg5ZGU4OGY4NmZiIiwidGFnIjoiIn0%3D; expires=Mon, 03-Mar-2025 08:47:59 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImpOSTZ4V041ejkwbkRudUxBV0FjTFE9PSIsInZhbHVlIjoiUllJK1FJK0JSckcxQ2tZQlRoZGRNRW0veTJiZjNodmlpaHlhQlhYUkNTa3piUmMwdkZOYVZkd1pzM0VoYXVkVDlDT3J1N" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkRyazZqcForeU1vV2ttcFhzbzF5Ymc9PSIsInZhbHVlIjoiY0p4clVpTWJJWTdoaEFtRGowSFhZRGEzMHhjejB6MzFSbURlVFNzSXFYSUJxRTd0cnhWTC83T3hVVklCRVFFRUFkWlVyc29tdkxGc0dXOEpvRkVaRm1sN293UitxalVxQmJ3bkRLYWYzanhPNnAxTTN0WEtwN1lPNnRvWTV3ajYiLCJtYWMiOiI0NDU0YzdmODM1MjQxYjQxYjYxNTlkZWQ0ZGIzZmQyOWUwNmFkZTk1YzMzNWI2NTVmYzdlNmIxZWM3ZjEyMzgwIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkRyazZqcForeU1vV2ttcFhzbzF5Ymc9PSIsInZhbHVlIjoiY0p4clVpTWJJWTdoaEFtRGowSFhZRGEzMHhjejB6MzFSbURlVFNzSXFYSUJxRTd0cnhWTC83T3h" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "tzItREzwxTMjvoW9461d7ZSRCwxW4tGpBsKgwURs" "uc_cart_id" => "dcb918d7f954dbd458ac622181e4bfe5" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/122027" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-28 20:47:59GET/article/122027414361