Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression

Author(s): Saurabh Satija*, Harpreet Kaur, Murtaza M. Tambuwala, Prabal Sharma, Manish Vyas, Navneet Khurana, Neha Sharma, Hamid A. Bakshi, Nitin B. Charbe, Flavia C. Zacconi, Alaa A. Aljabali, Srinivas Nammi, Harish Dureja, Thakur G. Singh, Gaurav Gupta, Daljeet S. Dhanjal, Kamal Dua, Dinesh K. Chellappan* and Meenu Mehta*

Volume 14, Issue 3, 2021

Published on: 20 January, 2021

Page: [321 - 332] Pages: 12

DOI: 10.2174/1874467214666210120154929

Price: $65

Abstract

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

Keywords: Hypoxia, normoxia, microenvironment, tumor, HIF, hydroxylation, cancer progression.

Graphical Abstract

[1]
Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med., 2013, 19(11), 1423-1437.
[http://dx.doi.org/10.1038/nm.3394] [PMID: 24202395]
[2]
Brown, J.M.; Wilson, W.R. Exploiting tumour hypoxia in cancer treatment. Nat. Rev. Cancer, 2004, 4(6), 437-447.
[http://dx.doi.org/10.1038/nrc1367] [PMID: 15170446]
[3]
Hinge, N.; Pandey, M.M.; Singhvi, G.; Gupta, G.; Mehta, M.; Satija, S.; Gulati, M.; Dureja, H.; Dua, K. Nanomedicine Advances in Cancer Therapy. Advanced 3D-Printed Systems and Nanosystems for Drug Delivery and Tissue Engineering; du Toit, L.C.; Kumar, P.; Choonara, Y.E.; Pillay, V., Eds.; Elsevier, 2020, pp. 219-253.
[http://dx.doi.org/10.1016/B978-0-12-818471-4.00008-X]
[4]
Tan, Y.Y.; Yap, P.K.; Xin Lim, G.L.; Mehta, M.; Chan, Y.; Ng, S.W.; Kapoor, D.N.; Negi, P.; Anand, K.; Singh, S.K.; Jha, N.K.; Lim, L.C.; Madheswaran, T.; Satija, S.; Gupta, G.; Dua, K.; Chellappan, D.K. Perspectives and advancements in the design of nanomaterials for targeted cancer theranostics. Chem. Biol. Interact., 2020, 329109221
[http://dx.doi.org/10.1016/j.cbi.2020.109221] [PMID: 32768398]
[5]
Hardwick, J.; Taylor, J.; Mehta, M.; Satija, S.; Paudel, K.R.; Hansbro, P.M.; Chellappan, D.K.; Bebawy, M.; Dua, K. Targeting Cancer using Curcumin Encapsulated Vesicular Drug Delivery Systems. Curr. Pharm. Des., 2020, 26.
[http://dx.doi.org/10.2174/1381612826666200728151610] [PMID: 32723255]
[6]
Aggarwal, T.; Wadhwa, R.; Gupta, R.; Paudel, K.R.; Collet, T.; Chellappan, D.K.; Gupta, G.; Perumalsamy, H.; Mehta, M.; Satija, S.; Hansbro, P.M.; Dua, K.; Maurya, P.K. MicroRNAs as Biomarker for Breast Cancer. Endocr. Metab. Immune Disord. Drug Targets, 2020, 20(10), 1597-1610.
[http://dx.doi.org/10.2174/1871530320666200428113051] [PMID: 32342824]
[7]
Shannon, A.M.; Bouchier-Hayes, D.J.; Condron, C.M.; Toomey, D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat. Rev., 2003, 29(4), 297-307.
[http://dx.doi.org/10.1016/S0305-7372(03)00003-3] [PMID: 12927570]
[8]
Vaupel, P.; Harrison, L. Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist, 2004, 9(Suppl. 5), 4-9.
[http://dx.doi.org/10.1634/theoncologist.9-90005-4] [PMID: 15591417]
[9]
Sharma, P.; Mehta, M.; Dhanjal, D.S.; Kaur, S.; Gupta, G.; Singh, H.; Thangavelu, L.; Rajeshkumar, S.; Tambuwala, M.; Bakshi, H.A.; Chellappan, D.K.; Dua, K.; Satija, S. Emerging trends in the novel drug delivery approaches for the treatment of lung cancer. Chem. Biol. Interact., 2019, 309108720
[http://dx.doi.org/10.1016/j.cbi.2019.06.033] [PMID: 31226287]
[10]
Bakshi, H.A.; Mishra, V.; Satija, S.; Mehta, M.; Hakkim, F.L.; Kesharwani, P.; Dua, K.; Chellappan, D.K.; Charbe, N.B.; Shrivastava, G.; Rajeshkumar, S.; Aljabali, A.A.; Al-Trad, B.; Pabreja, K.; Tambuwala, M.M. Dynamics of Prolyl Hydroxylases Levels During Disease Progression in Experimental Colitis. Inflammation, 2019, 42(6), 2032-2036.
[http://dx.doi.org/10.1007/s10753-019-01065-3] [PMID: 31377947]
[11]
Aljabali, A.A.A.; Bakshi, H.A.; Hakkim, F.L.; Haggag, Y.A.; Albatanyeh, K.M.; Al Zoubi, M.S.; Al-Trad, B.; Nasef, M.M.; Satija, S.; Mehta, M.; Pabreja, K.; Mishra, V.; Khan, M.; Abobaker, S.; Azzouz, I.M.; Dureja, H.; Pabari, R.M.; Dardouri, A.A.K.; Kesharwani, P.; Gupta, G.; Shukla, S.D.; Prasher, P.; Charbe, N.B.; Negi, P.; Kapoor, D.N.; Chellappan, D.K.; da Silva, M.W.; Thompson, P.; Dua, K.; McCarron, P.; Tambuwala, M.M. Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer via Downregulation of Nuclear P65 and HIF-1α. Cancers (Basel), 2020, 12, 113.
[http://dx.doi.org/10.3390/cancers12010113]
[12]
Höckel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst., 2001, 93(4), 266-276.
[http://dx.doi.org/10.1093/jnci/93.4.266] [PMID: 11181773]
[13]
Dua, K.; Wadhwa, R.; Singhvi, G.; Rapalli, V.; Shukla, S.D.; Shastri, M.D.; Gupta, G.; Satija, S.; Mehta, M.; Khurana, N.; Awasthi, R.; Maurya, P.K.; Thangavelu, L.; S, R.; Tambuwala, M.M.; Collet, T.; Hansbro, P.M.; Chellappan, D.K. The potential of siRNA based drug delivery in respiratory disorders: Recent advances and progress. Drug Dev. Res., 2019, 80(6), 714-730.
[http://dx.doi.org/10.1002/ddr.21571] [PMID: 31691339]
[14]
Gupta, P.; Gupta, A.; Agarwal, K.; Tomar, P.; Satija, S. Antioxidant and cytotoxic potential of a new thienyl derivative from Tagetes erecta roots. Pharm. Biol., 2012, 50(8), 1013-1018.
[http://dx.doi.org/10.3109/13880209.2012.655378] [PMID: 22775418]
[15]
Mehta, M.; Satija, S.; Kalsi, V. Invitro Antioxidant Evaluation of Psidium Guajava Strem Extracts. Int. J. Drug Dev. Res., 2011, 3, 213-216.
[16]
Bakshi, H.A.; Zoubi, M.S.A.; Hakkim, F.L.; Aljabali, A.A.A.; Rabi, F.A.; Hafiz, A.A.; Al-Batanyeh, K.M.; Al-Trad, B.; Ansari, P.; Nasef, M.M.; Charbe, N.B.; Satija, S.; Mehta, M.; Mishra, V.; Gupta, G.; Abobaker, S.; Negi, P.; Azzouz, I.M.; Dardouri, A.A.K.; Dureja, H.; Prasher, P.; Chellappan, D.K.; Dua, K.; Webba da Silva, M.; El Tanani, M.; McCarron, P.A.; Tambuwala, M.M.; Dietary Crocin Is Protective, M. Dietary crocin is protective in pancreatic cancer while reducing radiation-induced hepatic oxidative damage. Nutrients, 2020, 12(6), 1901.
[http://dx.doi.org/10.3390/nu12061901] [PMID: 32604971]
[17]
Garg, M.; Lata, K.; Satija, S. Cytotoxic potential of few Indian fruit peels through 3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide assay on HepG2 cells. Indian J. Pharmacol., 2016, 48(1), 64-68.
[http://dx.doi.org/10.4103/0253-7613.174552] [PMID: 26997725]
[18]
Mehta, M.; Satija, S.; Nanda, A.; Garg, M. Nanotechnologies for boswellic acids. Am. J. Drug Discov. Dev., 2014, 4, 1-11.
[http://dx.doi.org/10.3923/ajdd.2014.1.11]
[19]
Mehta, M.; Deeksha, ; Sharma, N.; Vyas, M.; Khurana, N.; Maurya, P.K.; Singh, H.; Andreoli de Jesus, T.P.; Dureja, H.; Chellappan, D.K.; Gupta, G.; Wadhwa, R.; Collet, T.; Hansbro, P.M.; Dua, K.; Satija, S. Interactions with the macrophages: An emerging targeted approach using novel drug delivery systems in respiratory diseases. Chem. Biol. Interact., 2019, 304, 10-19.
[http://dx.doi.org/10.1016/j.cbi.2019.02.021] [PMID: 30849336]
[20]
Kumar, P.; Mehta, M.; Satija, S.; Garg, M. Enzymatic in vitro anti-diabetic activity of few traditional indian medicinal plants. J. Biol. Sci., 2013, 13, 540-544.
[http://dx.doi.org/10.3923/jbs.2013.540.544]
[21]
Blancher, C.; Harris, A.L. The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target. Cancer Metastasis Rev., 1998, 17(2), 187-194.
[http://dx.doi.org/10.1023/A:1006002419244] [PMID: 9770115]
[22]
Rademakers, S.E.; Span, P.N.; Kaanders, J.H.A.M.; Sweep, F.C.G.J.; van der Kogel, A.J.; Bussink, J. Molecular aspects of tumour hypoxia. Mol. Oncol., 2008, 2(1), 41-53.
[http://dx.doi.org/10.1016/j.molonc.2008.03.006] [PMID: 19383328]
[23]
Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis, 2018, 7(1), 10.
[http://dx.doi.org/10.1038/s41389-017-0011-9] [PMID: 29362402]
[24]
Yang, C.S.; Wang, H.; Chen, J.X.; Zhang, J. Natural products and cancer signaling: Isoprenoids. Polyphenols and Flavonoids, 2014.
[25]
Semenza, G.L. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda), 2009, 24, 97-106.
[http://dx.doi.org/10.1152/physiol.00045.2008] [PMID: 19364912]
[26]
Reeves, K.J.; Brown, N.J. Hypoxia and Angiogenesis: From Primary Tumor to Bone Metastasis.Bone Cancer: Primary Bone Cancers and Bone Metastases, 2nd ed; Heymann, D., Ed.; Academic Press, 2015, pp. 177-189.
[http://dx.doi.org/10.1016/B978-0-12-416721-6.00016-9]
[27]
Semenza, G. Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol., 2002, 64(5-6), 993-998.
[http://dx.doi.org/10.1016/S0006-2952(02)01168-1] [PMID: 12213597]
[28]
Rankin, E.B.; Giaccia, A.J. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ., 2008, 15(4), 678-685.
[http://dx.doi.org/10.1038/cdd.2008.21] [PMID: 18259193]
[29]
Brahimi-Horn, C.; Pouysségur, J. The role of the hypoxia-inducible factor in tumor metabolism growth and invasion. Bull. Cancer, 2006, 93(8), E73-E80.
[PMID: 16935775]
[30]
Brahimi-Horn, M.C.; Pouysségur, J. The hypoxia-inducible factor and tumor progression along the angiogenic pathway. Int. Rev. Cytol., 2005, 242, 157-213.
[http://dx.doi.org/10.1016/S0074-7696(04)42004-X] [PMID: 15598469]
[31]
Masoud, G.N.; Li, W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B, 2015, 5(5), 378-389.
[http://dx.doi.org/10.1016/j.apsb.2015.05.007] [PMID: 26579469]
[32]
Semenza, G.L. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb. Symp. Quant. Biol., 2011, 76, 347-353.
[http://dx.doi.org/10.1101/sqb.2011.76.010678] [PMID: 21785006]
[33]
Semenza, G.L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev., 2010, 20(1), 51-56.
[http://dx.doi.org/10.1016/j.gde.2009.10.009] [PMID: 19942427]
[34]
Toffoli, S.; Roegiers, A.; Feron, O.; Van Steenbrugge, M.; Ninane, N.; Raes, M.; Michiels, C. Intermittent hypoxia is an angiogenic inducer for endothelial cells: role of HIF-1. Angiogenesis, 2009, 12(1), 47-67.
[http://dx.doi.org/10.1007/s10456-009-9131-y] [PMID: 19184477]
[35]
Krock, B.L.; Skuli, N.; Simon, M.C. Hypoxia-induced angiogenesis: Good and evil. Genes Cancer, 2011, 2(12), 1117-1133.
[http://dx.doi.org/10.1177/1947601911423654] [PMID: 22866203]
[36]
Pugh, C.W.; Ratcliffe, P.J. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat. Med., 2003, 9(6), 677-684.
[http://dx.doi.org/10.1038/nm0603-677] [PMID: 12778166]
[37]
Conway, E.M.; Collen, D.; Carmeliet, P. Molecular mechanisms of blood vessel growth. Cardiovasc. Res., 2001, 49(3), 507-521.
[http://dx.doi.org/10.1016/S0008-6363(00)00281-9] [PMID: 11166264]
[38]
Semenza, G.L. Expression of hypoxia-inducible factor 1: Mechanisms and consequences. Biochem. Pharmacol., 2000, 59(1), 47-53.
[http://dx.doi.org/10.1016/S0006-2952(99)00292-0] [PMID: 10605934]
[39]
Richard, D.E.; Berra, E.; Pouysségur, J. Angiogenesis: How a tumor adapts to hypoxia. Biochem. Biophys. Res. Commun., 1999, 266(3), 718-722.
[http://dx.doi.org/10.1006/bbrc.1999.1889] [PMID: 10603309]
[40]
Huang, L.E.; Bunn, H.F. Hypoxia-inducible factor and its biomedical relevance. J. Biol. Chem., 2003, 278(22), 19575-19578.
[http://dx.doi.org/10.1074/jbc.R200030200] [PMID: 12639949]
[41]
Harris, A.L. Hypoxia- a key regulatory factor in tumour growth. Nat. Rev. Cancer, 2002, 2(1), 38-47.
[http://dx.doi.org/10.1038/nrc704] [PMID: 11902584]
[42]
Caniggia, I.; Mostachfi, H.; Winter, J.; Gassmann, M.; Lye, S.J.; Kuliszewski, M.; Post, M. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J. Clin. Invest., 2000, 105(5), 577-587.
[http://dx.doi.org/10.1172/JCI8316] [PMID: 10712429]
[43]
Iyer, N.V.; Kotch, L.E.; Agani, F.; Leung, S.W.; Laughner, E.; Wenger, R.H.; Gassmann, M.; Gearhart, J.D.; Lawler, A.M.; Yu, A.Y.; Semenza, G.L. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 α. Genes Dev., 1998, 12(2), 149-162.
[http://dx.doi.org/10.1101/gad.12.2.149] [PMID: 9436976]
[44]
Ryan, H.E.; Lo, J.; Johnson, R.S. HIF-1 α is required for solid tumor formation and embryonic vascularization. EMBO J., 1998, 17(11), 3005-3015.
[http://dx.doi.org/10.1093/emboj/17.11.3005] [PMID: 9606183]
[45]
Carmeliet, P.; Dor, Y.; Herbert, J.M.; Fukumura, D.; Brusselmans, K.; Dewerchin, M.; Neeman, M.; Bono, F.; Abramovitch, R.; Maxwell, P.; Koch, C.J.; Ratcliffe, P.; Moons, L.; Jain, R.K.; Collen, D.; Keshert, E. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature, 1998, 394(6692), 485-490.
[http://dx.doi.org/10.1038/28867] [PMID: 9697772]
[46]
Wykoff, C.C.; Pugh, C.W.; Maxwell, P.H.; Harris, A.L.; Ratcliffe, P.J. Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene, 2000, 19(54), 6297-6305.
[http://dx.doi.org/10.1038/sj.onc.1204012] [PMID: 11175344]
[47]
Cormier-Regard, S.; Nguyen, S.V.; Claycomb, W.C. Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J. Biol. Chem., 1998, 273(28), 17787-17792.
[http://dx.doi.org/10.1074/jbc.273.28.17787] [PMID: 9651380]
[48]
LeCouter, J.; Kowalski, J.; Foster, J.; Hass, P.; Zhang, Z.; Dillard-Telm, L.; Frantz, G.; Rangell, L.; DeGuzman, L.; Keller, G.A.; Peale, F.; Gurney, A.; Hillan, K.J.; Ferrara, N. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature, 2001, 412(6850), 877-884.
[http://dx.doi.org/10.1038/35091000] [PMID: 11528470]
[49]
Jiang, B.H.; Rue, E.; Wang, G.L.; Roe, R.; Semenza, G.L. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem., 1996, 271(30), 17771-17778.
[http://dx.doi.org/10.1074/jbc.271.30.17771] [PMID: 8663540]
[50]
Feldser, D.; Agani, F.; Iyer, N.V.; Pak, B.; Ferreira, G.; Semenza, G.L. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res., 1999, 59(16), 3915-3918.
[PMID: 10463582]
[51]
Tazuke, S.I.; Mazure, N.M.; Sugawara, J.; Carland, G.; Faessen, G.H.; Suen, L.F.; Irwin, J.C.; Powell, D.R.; Giaccia, A.J.; Giudice, L.C. Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: A possible model for IGFBP-1 expression in fetal hypoxia. Proc. Natl. Acad. Sci. USA, 1998, 95(17), 10188-10193.
[http://dx.doi.org/10.1073/pnas.95.17.10188] [PMID: 9707622]
[52]
Melillo, G.; Musso, T.; Sica, A.; Taylor, L.S.; Cox, G.W.; Varesio, L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J. Exp. Med., 1995, 182(6), 1683-1693.
[http://dx.doi.org/10.1084/jem.182.6.1683] [PMID: 7500013]
[53]
Palmer, L.A.; Semenza, G.L.; Stoler, M.H.; Johns, R.A. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am. J. Physiol., 1998, 274(2), L212-L219.
[PMID: 9486205]
[54]
Nordgren, I.K.; Tavassoli, A. Targeting tumour angiogenesis with small molecule inhibitors of hypoxia inducible factor. Chem. Soc. Rev., 2011, 40(8), 4307-4317.
[http://dx.doi.org/10.1039/c1cs15032d] [PMID: 21483947]
[55]
De Bels, D.; Corazza, F.; Balestra, C. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med., 2011, 365(19), 1845-1846.
[http://dx.doi.org/10.1056/NEJMc1110602] [PMID: 22070493]
[56]
Semenza, G.L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol., 2014, 9, 47-71.
[http://dx.doi.org/10.1146/annurev-pathol-012513-104720] [PMID: 23937437]
[57]
Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA, 1995, 92(12), 5510-5514.
[http://dx.doi.org/10.1073/pnas.92.12.5510] [PMID: 7539918]
[58]
Ziello, J.E.; Jovin, I.S.; Huang, Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J. Biol. Med., 2007, 80(2), 51-60.
[PMID: 18160990]
[59]
Dales, J.P.; Garcia, S.; Meunier-Carpentier, S.; Andrac-Meyer, L.; Haddad, O.; Lavaut, M.N.; Allasia, C.; Bonnier, P.; Charpin, C. Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: Retrospective study in a series of 745 patients. Int. J. Cancer, 2005, 116(5), 734-739.
[http://dx.doi.org/10.1002/ijc.20984] [PMID: 15849727]
[60]
Semenza, G.L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol., 2000, 35(2), 71-103.
[http://dx.doi.org/10.1080/10409230091169186] [PMID: 10821478]
[61]
Zhong, H.; De Marzo, A.M.; Laughner, E.; Lim, M.; Hilton, D.A.; Zagzag, D.; Buechler, P.; Isaacs, W.B.; Semenza, G.L.; Simons, J.W. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res., 1999, 59(22), 5830-5835.
[PMID: 10582706]
[62]
Semenza, G.L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene, 2010, 29(5), 625-634.
[http://dx.doi.org/10.1038/onc.2009.441] [PMID: 19946328]
[63]
Höckel, M.; Vaupel, P. Biological consequences of tumor hypoxia. Semin. Oncol., 2001, 28(2)(Suppl. 8), 36-41.
[http://dx.doi.org/10.1016/S0093-7754(01)90211-8] [PMID: 11395851]
[64]
Lum, J.J.; Bui, T.; Gruber, M.; Gordan, J.D.; DeBerardinis, R.J.; Covello, K.L.; Simon, M.C.; Thompson, C.B. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev., 2007, 21(9), 1037-1049.
[http://dx.doi.org/10.1101/gad.1529107] [PMID: 17437992]
[65]
Beischlag, T.V.; Luis Morales, J.; Hollingshead, B.D.; Perdew, G.H. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr., 2008, 18(3), 207-250.
[http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v18.i3.20] [PMID: 18540824]
[66]
Hankinson, O. The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol., 1995, 35, 307-340.
[http://dx.doi.org/10.1146/annurev.pa.35.040195.001515] [PMID: 7598497]
[67]
Hahn, M.E. The aryl hydrocarbon receptor: a comparative perspective. Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol., 1998, 121(1-3), 23-53.
[http://dx.doi.org/10.1016/S0742-8413(98)10028-2] [PMID: 9972449]
[68]
Wu, D.; Potluri, N.; Kim, Y.; Rastinejad, F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Mol. Cell. Biol., 2013, 33(21), 4346-4356.
[http://dx.doi.org/10.1128/MCB.00698-13] [PMID: 24001774]
[69]
Lavista-Llanos, S.; Centanin, L.; Irisarri, M.; Russo, D.M.; Gleadle, J.M.; Bocca, S.N.; Muzzopappa, M.; Ratcliffe, P.J.; Wappner, P. Control of the hypoxic response in Drosophila melanogaster by the basic helix-loop-helix PAS protein similar. Mol. Cell. Biol., 2002, 22(19), 6842-6853.
[http://dx.doi.org/10.1128/MCB.22.19.6842-6853.2002] [PMID: 12215541]
[70]
Wang, G.L.; Semenza, G.L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem., 1995, 270(3), 1230-1237.
[http://dx.doi.org/10.1074/jbc.270.3.1230] [PMID: 7836384]
[71]
Semenza, G.L.; Agani, F.; Booth, G.; Forsythe, J.; Iyer, N.; Jiang, B.H.; Leung, S.; Roe, R.; Wiener, C.; Yu, A. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int., 1997, 51(2), 553-555.
[http://dx.doi.org/10.1038/ki.1997.77] [PMID: 9027737]
[72]
Erbel, P.J.A.; Card, P.B.; Karakuzu, O.; Bruick, R.K.; Gardner, K.H. Structural basis for PAS domain heterodimerization in the basic helix- loop- helix-PAS transcription factor hypoxia-inducible factor. Proc. Natl. Acad. Sci. USA, 2003, 100(26), 15504-15509.
[http://dx.doi.org/10.1073/pnas.2533374100] [PMID: 14668441]
[73]
Zhulin, I.B.; Taylor, B.L.; Dixon, R. PAS domain S-boxes in archaea, bacteria and sensors for oxygen and redox. Trends Biochem. Sci., 1997, 22(9), 331-333.
[http://dx.doi.org/10.1016/S0968-0004(97)01110-9] [PMID: 9301332]
[74]
Ponting, C.P.; Aravind, L. PAS: a multifunctional domain family comes to light. Curr. Biol., 1997, 7(11), R674-R677.
[http://dx.doi.org/10.1016/S0960-9822(06)00352-6] [PMID: 9382818]
[75]
Yang, J.; Zhang, L.; Erbel, P.J.A.; Gardner, K.H.; Ding, K.; Garcia, J.A.; Bruick, R.K. Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor. J. Biol. Chem., 2005, 280(43), 36047-36054.
[http://dx.doi.org/10.1074/jbc.M501755200] [PMID: 16129688]
[76]
Li, H.; Ko, H.P.; Whitlock, J.P. Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of Arnt and HIF1α. J. Biol. Chem., 1996, 271(35), 21262-21267.
[http://dx.doi.org/10.1074/jbc.271.35.21262] [PMID: 8702901]
[77]
Kallio, P.J.; Okamoto, K.; O’Brien, S.; Carrero, P.; Makino, Y.; Tanaka, H.; Poellinger, L. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J., 1998, 17(22), 6573-6586.
[http://dx.doi.org/10.1093/emboj/17.22.6573] [PMID: 9822602]
[78]
Bruick, R.K.; McKnight, S.L. A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF. Science (80-. ), 2001, 294, 1337-1340.
[79]
Wang, G.L.; Jiang, B-H.; Rue, E.A.; Semenza, G.L. Hypoxia-Inducible Factor 1 Is a Basic-Helix-Loop-Helix-PAS Heterodimer Regulated by Cellular 02 Tension (Dioxin Receptor/Erythropoietin/Hypoxia/Transcription). Genetics, 1995, 92, 5510-5514.
[80]
Wu, D.; Potluri, N.; Lu, J.; Kim, Y.; Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature, 2015, 524(7565), 303-308.
[http://dx.doi.org/10.1038/nature14883] [PMID: 26245371]
[81]
Huang, Z.J.; Edery, I.; Rosbash, M. PAS is a dimerization domain common to Drosophila period and several transcription factors. Nature, 1993, 364(6434), 259-262.
[http://dx.doi.org/10.1038/364259a0] [PMID: 8391649]
[82]
Tian, H.; McKnight, S.L.; Russell, D.W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev., 1997, 11(1), 72-82.
[http://dx.doi.org/10.1101/gad.11.1.72] [PMID: 9000051]
[83]
Wiesener, M.S.; Turley, H.; Allen, W.E.; Willam, C.; Eckardt, K.U.; Talks, K.L.; Wood, S.M.; Gatter, K.C.; Harris, A.L.; Pugh, C.W.; Ratcliffe, P.J.; Maxwell, P.H. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood, 1998, 92(7), 2260-2268.
[http://dx.doi.org/10.1182/blood.V92.7.2260] [PMID: 9746763]
[84]
Makino, Y.; Cao, R.; Svensson, K.; Bertilsson, G.; Asman, M.; Tanaka, H.; Cao, Y.; Berkenstam, A.; Poellinger, L. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature, 2001, 414(6863), 550-554.
[http://dx.doi.org/10.1038/35107085] [PMID: 11734856]
[85]
Wiesener, M.S.; Jürgensen, J.S.; Rosenberger, C.; Scholze, C.K.; Hörstrup, J.H.; Warnecke, C.; Mandriota, S.; Bechmann, I.; Frei, U.A.; Pugh, C.W.; Ratcliffe, P.J.; Bachmann, S.; Maxwell, P.H.; Eckardt, K.U. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J., 2003, 17(2), 271-273.
[http://dx.doi.org/10.1096/fj.02-0445fje] [PMID: 12490539]
[86]
Ema, M.; Taya, S.; Yokotani, N.; Sogawa, K.; Matsuda, Y.; Fujii-Kuriyama, Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl. Acad. Sci. USA, 1997, 94(9), 4273-4278.
[http://dx.doi.org/10.1073/pnas.94.9.4273] [PMID: 9113979]
[87]
Fukuda, R.; Hirota, K.; Fan, F.; Jung, Y.D.; Ellis, L.M.; Semenza, G.L. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem., 2002, 277(41), 38205-38211.
[http://dx.doi.org/10.1074/jbc.M203781200] [PMID: 12149254]
[88]
Treins, C.; Giorgetti-Peraldi, S.; Murdaca, J.; Semenza, G.L.; Van Obberghen, E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem., 2002, 277(31), 27975-27981.
[http://dx.doi.org/10.1074/jbc.M204152200] [PMID: 12032158]
[89]
Jun, J.C.; Rathore, A.; Younas, H.; Gilkes, D.; Polotsky, V.Y. Hypoxia-Inducible Factors and Cancer. Curr. Sleep Med. Rep., 2017, 3(1), 1-10.
[http://dx.doi.org/10.1007/s40675-017-0062-7] [PMID: 28944164]
[90]
Masson, N.; Willam, C.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J., 2001, 20(18), 5197-5206.
[http://dx.doi.org/10.1093/emboj/20.18.5197] [PMID: 11566883]
[91]
Marxsen, J.H.; Stengel, P.; Doege, K.; Heikkinen, P.; Jokilehto, T.; Wagner, T.; Jelkmann, W.; Jaakkola, P.; Metzen, E. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases. Biochem. J., 2004, 381(Pt 3), 761-767.
[http://dx.doi.org/10.1042/BJ20040620] [PMID: 15104534]
[92]
Manalo, D.J.; Rowan, A.; Lavoie, T.; Natarajan, L.; Kelly, B.D.; Ye, S.Q.; Garcia, J.G.N.; Semenza, G.L. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood, 2005, 105(2), 659-669.
[http://dx.doi.org/10.1182/blood-2004-07-2958] [PMID: 15374877]
[93]
Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, J. HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing. Science, 2001, 292, 464-468.
[94]
Yu, F.; White, S.B.; Zhao, Q.; Lee, F.S. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl. Acad. Sci. USA, 2001, 98(17), 9630-9635.
[http://dx.doi.org/10.1073/pnas.181341498] [PMID: 11504942]
[95]
Epstein, A.C.R.; Gleadle, J.M.; McNeill, L.A.; Hewitson, K.S.; O’Rourke, J.; Mole, D.R.; Mukherji, M.; Metzen, E.; Wilson, M.I.; Dhanda, A.; Tian, Y.M.; Masson, N.; Hamilton, D.L.; Jaakkola, P.; Barstead, R.; Hodgkin, J.; Maxwell, P.H.; Pugh, C.W.; Schofield, C.J.; Ratcliffe, P.J.C. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 2001, 107(1), 43-54.
[http://dx.doi.org/10.1016/S0092-8674(01)00507-4] [PMID: 11595184]
[96]
Schofield, C.J.; Ratcliffe, P.J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol., 2004, 5(5), 343-354.
[http://dx.doi.org/10.1038/nrm1366] [PMID: 15122348]
[97]
Huang, J.; Zhao, Q.; Mooney, S.M.; Lee, F.S. Sequence determinants in hypoxia-inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J. Biol. Chem., 2002, 277(42), 39792-39800.
[http://dx.doi.org/10.1074/jbc.M206955200] [PMID: 12181324]
[98]
Kageyama, Y.; Koshiji, M.; To, K.K.W.; Tian, Y.M.; Ratcliffe, P.J.; Huang, L.E. Leu-574 of human HIF-1α is a molecular determinant of prolyl hydroxylation. FASEB J., 2004, 18(9), 1028-1030.
[http://dx.doi.org/10.1096/fj.03-1233fje] [PMID: 15084514]
[99]
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer, 2003, 3(10), 721-732.
[http://dx.doi.org/10.1038/nrc1187] [PMID: 13130303]
[100]
Jeong, J.W.; Bae, M.K.; Ahn, M.Y.; Kim, S.H.; Sohn, T.K.; Bae, M.H.; Yoo, M.A.; Song, E.J.; Lee, K.J.; Kim, K.W. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell, 2002, 111(5), 709-720.
[http://dx.doi.org/10.1016/S0092-8674(02)01085-1] [PMID: 12464182]
[101]
Huang, L.E.; Gu, J.; Schau, M.; Bunn, H.F. Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA, 1998, 95(14), 7987-7992.
[http://dx.doi.org/10.1073/pnas.95.14.7987] [PMID: 9653127]
[102]
Kallio, P.J.; Wilson, W.J.; O’Brien, S.; Makino, Y.; Poellinger, L. Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway. J. Biol. Chem., 1999, 274(10), 6519-6525.
[http://dx.doi.org/10.1074/jbc.274.10.6519] [PMID: 10037745]
[103]
Kondo, K.; Kaelin, W.G., Jr The von Hippel-Lindau tumor suppressor gene. Exp. Cell Res., 2001, 264(1), 117-125.
[http://dx.doi.org/10.1006/excr.2000.5139] [PMID: 11237528]
[104]
Kamura, T.; Sato, S.; Iwai, K.; Czyzyk-Krzeska, M.; Conaway, R.C.; Conaway, J.W. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc. Natl. Acad. Sci. USA, 2000, 97(19), 10430-10435.
[http://dx.doi.org/10.1073/pnas.190332597] [PMID: 10973499]
[105]
Cockman, M.E.; Masson, N.; Mole, D.R.; Jaakkola, P.; Chang, G.W.; Clifford, S.C.; Maher, E.R.; Pugh, C.W.; Ratcliffe, P.J.; Maxwell, P.H. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem., 2000, 275(33), 25733-25741.
[http://dx.doi.org/10.1074/jbc.M002740200] [PMID: 10823831]
[106]
Ohh, M.; Park, C.W.; Ivan, M.; Hoffman, M.A.; Kim, T.Y.; Huang, L.E.; Pavletich, N.; Chau, V.; Kaelin, W.G. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel-Lindau protein. Nat. Cell Biol., 2000, 2(7), 423-427.
[http://dx.doi.org/10.1038/35017054] [PMID: 10878807]
[107]
Tanimoto, K.; Makino, Y.; Pereira, T.; Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J., 2000, 19(16), 4298-4309.
[http://dx.doi.org/10.1093/emboj/19.16.4298] [PMID: 10944113]
[108]
Willam, C.; Masson, N.; Tian, Y.M.; Mahmood, S.A.; Wilson, M.I.; Bicknell, R.; Eckardt, K.U.; Maxwell, P.H.; Ratcliffe, P.J.; Pugh, C.W. Peptide blockade of HIFalpha degradation modulates cellular metabolism and angiogenesis. Proc. Natl. Acad. Sci. USA, 2002, 99(16), 10423-10428.
[http://dx.doi.org/10.1073/pnas.162119399] [PMID: 12149454]
[109]
Maxwell, P.H.; Wiesener, M.S.; Chang, G.W.; Clifford, S.C.; Vaux, E.C.; Cockman, M.E.; Wykoff, C.C.; Pugh, C.W.; Maher, E.R.; Ratcliffe, P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 1999, 399(6733), 271-275.
[http://dx.doi.org/10.1038/20459] [PMID: 10353251]
[110]
Lando, D.; Peet, D.J.; Whelan, D.A.; Gorman, J.J.; Whitelaw, M.L. Asparagine hydroxylation of the HIF transactivation domain: A hypoxic switch. Science, 2002, 295, 858-861.
[111]
Mahon, P.C.; Hirota, K.; Semenza, G.L. FIH-1: A novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev., 2001, 15(20), 2675-2686.
[http://dx.doi.org/10.1101/gad.924501] [PMID: 11641274]
[112]
Jiang, B.H.; Zheng, J.Z.; Leung, S.W.; Roe, R.; Semenza, G.L. Transactivation and inhibitory domains of hypoxia-inducible factor 1α. Modulation of transcriptional activity by oxygen tension. J. Biol. Chem., 1997, 272(31), 19253-19260.
[http://dx.doi.org/10.1074/jbc.272.31.19253] [PMID: 9235919]
[113]
Gu, J.; Milligan, J.; Huang, L.E. Molecular mechanism of hypoxia-inducible factor 1α -p300 interaction. A leucine-rich interface regulated by a single cysteine. J. Biol. Chem., 2001, 276(5), 3550-3554.
[http://dx.doi.org/10.1074/jbc.M009522200] [PMID: 11063749]
[114]
Lando, D.; Peet, D.J.; Gorman, J.J.; Whelan, D.A.; Whitelaw, M.L.; Bruick, R.K. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev., 2002, 16(12), 1466-1471.
[http://dx.doi.org/10.1101/gad.991402] [PMID: 12080085]
[115]
Hewitson, K.S.; McNeill, L.A.; Riordan, M.V.; Tian, Y.M.; Bullock, A.N.; Welford, R.W.; Elkins, J.M.; Oldham, N.J.; Bhattacharya, S.; Gleadle, J.M.; Ratcliffe, P.J.; Pugh, C.W.; Schofield, C.J. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem., 2002, 277(29), 26351-26355.
[http://dx.doi.org/10.1074/jbc.C200273200] [PMID: 12042299]
[116]
Wright, G.; Higgin, J.J.; Raines, R.T.; Steenbergen, C.; Murphy, E. Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, heme oxygenase-1, and nitric-oxide synthase proteins and confers protection from metabolic inhibition to cardiomyocytes. J. Biol. Chem., 2003, 278(22), 20235-20239.
[http://dx.doi.org/10.1074/jbc.M301391200] [PMID: 12649278]
[117]
Block, K.M.; Wang, H.; Szabó, L.Z.; Polaske, N.W.; Henchey, L.K.; Dubey, R.; Kushal, S.; László, C.F.; Makhoul, J.; Song, Z.; Meuillet, E.J.; Olenyuk, B.Z. Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. J. Am. Chem. Soc., 2009, 131(50), 18078-18088.
[http://dx.doi.org/10.1021/ja807601b] [PMID: 20000859]
[118]
Dann, C.E., III; Bruick, R.K.; Deisenhofer, J. Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15351-15356.
[http://dx.doi.org/10.1073/pnas.202614999] [PMID: 12432100]
[119]
McNeill, L.A.; Hewitson, K.S.; Claridge, T.D.; Seibel, J.F.; Horsfall, L.E.; Schofield, C.J. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the β-carbon of asparagine-803. Biochem. J., 2002, 367(Pt 3), 571-575.
[http://dx.doi.org/10.1042/bj20021162] [PMID: 12215170]
[120]
Yu, A.Y.; Frid, M.G.; Shimoda, L.A.; Wiener, C.M.; Stenmark, K.; Semenza, G.L. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am. J. Physiol., 1998, 275(4), L818-L826.
[PMID: 9755115]
[121]
Berra, E.; Richard, D.E.; Gothié, E.; Pouysségur, J. HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation. FEBS Lett., 2001, 491(1-2), 85-90.
[http://dx.doi.org/10.1016/S0014-5793(01)02159-7] [PMID: 11226425]
[122]
Jiang, B.H.; Jiang, G.; Zheng, J.Z.; Lu, Z.; Hunter, T.; Vogt, P.K. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ., 2001, 12(7), 363-369.
[PMID: 11457733]
[123]
Laughner, E.; Taghavi, P.; Chiles, K.; Mahon, P.C.; Semenza, G.L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: Novel mechanism for HIF-1- mediated vascular endothelial growth factor expression. Mol. Cell. Biol., 2001, 21(12), 3995-4004.
[http://dx.doi.org/10.1128/MCB.21.12.3995-4004.2001] [PMID: 11359907]
[124]
Berra, E.; Milanini, J.; Richard, D.E.; Le Gall, M.; Viñals, F.; Gothié, E.; Roux, D.; Pagès, G.; Pouysségur, J. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem. Pharmacol., 2000, 60(8), 1171-1178.
[http://dx.doi.org/10.1016/S0006-2952(00)00423-8] [PMID: 11007955]
[125]
Zundel, W.; Schindler, C.; Haas-Kogan, D.; Koong, A.; Kaper, F.; Chen, E.; Gottschalk, A.R.; Ryan, H.E.; Johnson, R.S.; Jefferson, A.B.; Stokoe, D.; Giaccia, A.J. Loss of PTEN facilitates HIF-1- mediated gene expression. Genes Dev., 2000, 14(4), 391-396.
[PMID: 10691731]
[126]
Sang, N.; Stiehl, D.P.; Bohensky, J.; Leshchinsky, I.; Srinivas, V.; Caro, J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J. Biol. Chem., 2003, 278(16), 14013-14019.
[http://dx.doi.org/10.1074/jbc.M209702200] [PMID: 12588875]
[127]
Hansson, L.O.; Friedler, A.; Freund, S.; Rüdiger, S.; Fersht, A.R. Two sequence motifs from HIF-1α bind to the DNA-binding site of p53. Proc. Natl. Acad. Sci. USA, 2002, 99(16), 10305-10309.
[http://dx.doi.org/10.1073/pnas.122347199] [PMID: 12124396]
[128]
Ravi, R.; Mookerjee, B.; Bhujwalla, Z.M.; Sutter, C.H.; Artemov, D.; Zeng, Q.; Dillehay, L.E.; Madan, A.; Semenza, G.L.; Bedi, A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev., 2000, 14(1), 34-44.
[PMID: 10640274]
[129]
Bech-Otschir, D.; Kraft, R.; Huang, X.; Henklein, P.; Kapelari, B.; Pollmann, C.; Dubiel, W. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J., 2001, 20(7), 1630-1639.
[http://dx.doi.org/10.1093/emboj/20.7.1630] [PMID: 11285227]
[130]
Bae, M.K.; Ahn, M.Y.; Jeong, J.W.; Bae, M.H.; Lee, Y.M.; Bae, S.K.; Park, J.W.; Kim, K.R.; Kim, K.W. Jab1 interacts directly with HIF-1α and regulates its stability. J. Biol. Chem., 2002, 277(1), 9-12.
[http://dx.doi.org/10.1074/jbc.C100442200] [PMID: 11707426]
[131]
Gradin, K.; McGuire, J.; Wenger, R.H.; Kvietikova, I.; fhitelaw, M.L.; Toftgård, R.; Tora, L.; Gassmann, M.; Poellinger, L. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol. Cell. Biol., 1996, 16(10), 5221-5231.
[http://dx.doi.org/10.1128/MCB.16.10.5221] [PMID: 8816435]
[132]
Isaacs, J.S.; Jung, Y.J.; Mimnaugh, E.G.; Martinez, A.; Cuttitta, F.; Neckers, L.M. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J. Biol. Chem., 2002, 277(33), 29936-29944.
[http://dx.doi.org/10.1074/jbc.M204733200] [PMID: 12052835]
[133]
Nagle, D.G.; Zhou, Y-D. Natural product-based inhibitors of hypoxia-inducible factor-1 (HIF-1). Curr. Drug Targets, 2006, 7(3), 355-369.
[http://dx.doi.org/10.2174/138945006776054979] [PMID: 16515532]
[134]
Wang, F.; Marshall, C.B.; Ikura, M. Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: Structural and functional versatility in target recognition. Cell. Mol. Life Sci., 2013, 70(21), 3989-4008.
[http://dx.doi.org/10.1007/s00018-012-1254-4] [PMID: 23307074]
[135]
Chowdhury, R.; Hardy, A.; Schofield, C.J. The human oxygen sensing machinery and its manipulation. Chem. Soc. Rev., 2008, 37(7), 1308-1319.
[http://dx.doi.org/10.1039/b701676j] [PMID: 18568157]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version503msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[18:11:28] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[18:11:28] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[18:11:28] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[18:11:28] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (128ms)time
  • Application (375ms)time
  • 1 x Application (74.49%)
    375ms
    1 x Booting (25.51%)
    128ms
    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
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated273ms
    • 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 ('59857113','',1,1739988688,1739988688) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739988688
      1.43msalphaeurekaselec_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 ('59857113','/article/113490',1,1739988688,1739988688)
      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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) 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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) 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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) 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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) 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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) 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 >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59857113 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59857113) limit 1
      19.03msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59857113
      • 1: 59857113
      • 2: 59857113
      • 3: 59857113
      • 4: 59857113
      • 5: 59857113
      • 6: 59857113
      • 7: 59857113
      • 8: 59857113
      • 9: 59857113
      • 10: 59857113
      • 11: 59857113
      • 12: 59857113
      • 13: 59857113
      • 14: 59857113
      • 15: 59857113
      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=113490
      1msalphaeurekaselec_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` = 98 limit 1
      23.14msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 98
      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=98) and sj.journal_id!=98 group by `j`.`nid`) as `aggregate_table`
      1.4msalphaeurekaselec_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=98) and sj.journal_id!=98 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      900μsalphaeurekaselec_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=98) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      970μsalphaeurekaselec_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=98) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      920μsalphaeurekaselec_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` = '113490'
      1.37msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 113490
      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` = '113490'
      29.19msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 113490
      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` = '113490' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.95msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 113490
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      320μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      670μsalphaeurekaselec_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 = 98 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      40.94msalphaeurekaselec_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 = 98 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      5.26msalphaeurekaselec_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 = 98 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      4.77msalphaeurekaselec_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` = 113490 limit 1
      240μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 113490
      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 = 113490 and content_type = 'article' order by status desc limit 1
      360μsalphaeurekaselec_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 = 436 and content_id!=113490 and cd.content_type = 'article' order by rand() limit 20
      115msalphaeurekaselec_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` = 190511 limit 1
      360μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 190511
      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` = 'CMP' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      360μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMP
      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 = '113490' 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) )
      1.31msalphaeurekaselec_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 = '10735' 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) )
      490μsalphaeurekaselec_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 = '2950' 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) )
      420μsalphaeurekaselec_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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2950) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2950) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2950)
      8.01msalphaeurekaselec_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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10735) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10735) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10735)
      830μsalphaeurekaselec_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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 113490) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 113490) 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 <= 59857113 and j.to_ip >=59857113 )) and ((j.from_date <= 1739988688 and j.to_date >= 1739988688 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 113490)
      800μsalphaeurekaselec_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` < '321' and is_uploaded = 1 and issue_id = 10735 order by cast(first_page as SIGNED) desc limit 1
      750μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 321
      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` > '332' and is_uploaded = 1 and issue_id = 10735 order by cast(first_page as SIGNED) asc limit 1
      660μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 332
      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'
      250μsalphaeurekaselec_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
      280μsalphaeurekaselec_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` = 113490 limit 1
      3.73msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 113490
      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` = 98 and `b`.`banner_from_date` <= 1739988688 and `b`.`banner_to_date` >= 1739988688 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.64msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 98
      • 3: 1739988688
      • 4: 1739988688
      • 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` = 98 and `b`.`banner_from_date` <= 1739988688 and `b`.`banner_to_date` >= 1739988688 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.58msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 98
      • 3: 1739988688
      • 4: 1739988688
      • 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='1d1afa5bd7249ca37c9ca204ebd71b24'
      240μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        JjBwUlFPmDkoMFNHT7CBwdmQ8XUyxifIPI3qwNlC
        uc_cart_id
        1d1afa5bd7249ca37c9ca204ebd71b24
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/113490" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/113490
        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 => "Wed, 19 Feb 2025 18:11:28 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjlHdldldWpFcXJpQXYxVDJSOHBxSmc9PSIsInZhbHVlIjoiRXBmeWFnSkwwU3ZTMTh2eXgvMjAyNkxNNWx0U0QyUENReW4zOFRDdE1ZeERib2V1bHN2clRNZmRwL1lLdkI5SDZRdHRXYktmUDhhMzVJL1pUQlpBRGdEVUVLMjN5RlFkU3hyTlR6NXBVVWEwczlOeGkzczF4aE01OXVoenRGek4iLCJtYWMiOiJiZGZjNTFhMWI3ODQ2MGE0NzhiMTBkMDcwMGNjNjRiZDc1MzJlNDhlNTM0ZjA2ODEyZmIyYjI5MTg3OWYwYTAwIiwidGFnIjoiIn0%3D; expires=Sat, 22 Feb 2025 06:11:28 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjlHdldldWpFcXJpQXYxVDJSOHBxSmc9PSIsInZhbHVlIjoiRXBmeWFnSkwwU3ZTMTh2eXgvMjAyNkxNNWx0U0QyUENReW4zOFRDdE1ZeERib2V1bHN2clRNZmRwL1lLdkI5SDZRdHRXY" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imt3UEFxajFLWWx6cVlvN25GRmYxY0E9PSIsInZhbHVlIjoiSWFMUXY3b05lTU1zRGJzVUtGMmRNNnZlS3VzWWZIZzdFVVVydzhvdVJIaXhwYmQ2YjEwUTBqaCt3T0l2eXgrOWZ5QXV2WGpMUFBJZ24vcm5XUG52bEk3cHpwQzRWazRyNStiUDdLZWtBQkRUZUNaZk1LTnE3SE8xZTVUc0xLa1giLCJtYWMiOiJmMjBhYjA1MmRlNDI4ZmNhM2ZhMmIxZGVhZjNhY2QyYjY1OTk1ZGZmMTU0NWE0YTlmY2YxYTUyNDUzMmEzNzRiIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Imt3UEFxajFLWWx6cVlvN25GRmYxY0E9PSIsInZhbHVlIjoiSWFMUXY3b05lTU1zRGJzVUtGMmRNNnZlS3VzWWZIZzdFVVVydzhvdVJIaXhwYmQ2YjEwUTBqaCt" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjlHdldldWpFcXJpQXYxVDJSOHBxSmc9PSIsInZhbHVlIjoiRXBmeWFnSkwwU3ZTMTh2eXgvMjAyNkxNNWx0U0QyUENReW4zOFRDdE1ZeERib2V1bHN2clRNZmRwL1lLdkI5SDZRdHRXYktmUDhhMzVJL1pUQlpBRGdEVUVLMjN5RlFkU3hyTlR6NXBVVWEwczlOeGkzczF4aE01OXVoenRGek4iLCJtYWMiOiJiZGZjNTFhMWI3ODQ2MGE0NzhiMTBkMDcwMGNjNjRiZDc1MzJlNDhlNTM0ZjA2ODEyZmIyYjI5MTg3OWYwYTAwIiwidGFnIjoiIn0%3D; expires=Sat, 22-Feb-2025 06:11:28 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjlHdldldWpFcXJpQXYxVDJSOHBxSmc9PSIsInZhbHVlIjoiRXBmeWFnSkwwU3ZTMTh2eXgvMjAyNkxNNWx0U0QyUENReW4zOFRDdE1ZeERib2V1bHN2clRNZmRwL1lLdkI5SDZRdHRXY" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imt3UEFxajFLWWx6cVlvN25GRmYxY0E9PSIsInZhbHVlIjoiSWFMUXY3b05lTU1zRGJzVUtGMmRNNnZlS3VzWWZIZzdFVVVydzhvdVJIaXhwYmQ2YjEwUTBqaCt3T0l2eXgrOWZ5QXV2WGpMUFBJZ24vcm5XUG52bEk3cHpwQzRWazRyNStiUDdLZWtBQkRUZUNaZk1LTnE3SE8xZTVUc0xLa1giLCJtYWMiOiJmMjBhYjA1MmRlNDI4ZmNhM2ZhMmIxZGVhZjNhY2QyYjY1OTk1ZGZmMTU0NWE0YTlmY2YxYTUyNDUzMmEzNzRiIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Imt3UEFxajFLWWx6cVlvN25GRmYxY0E9PSIsInZhbHVlIjoiSWFMUXY3b05lTU1zRGJzVUtGMmRNNnZlS3VzWWZIZzdFVVVydzhvdVJIaXhwYmQ2YjEwUTBqaCt" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "JjBwUlFPmDkoMFNHT7CBwdmQ8XUyxifIPI3qwNlC" "uc_cart_id" => "1d1afa5bd7249ca37c9ca204ebd71b24" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/113490" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 18:11:28GET/article/113490414371