Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

The Interactions among Hypertension, Cancer, and COVID-19: Perspective with Regard to Ca2+/cAMP Signalling

Author(s): Leandro Bueno Bergantin*

Volume 22, Issue 5, 2022

Published on: 26 April, 2022

Page: [351 - 360] Pages: 10

DOI: 10.2174/1568009622666220215143805

Price: $65

Abstract

Background: The hypothesis that hypertension is clinically associated with an enhanced risk of developing cancer has been highlighted. However, the working principles involved in this link are still under intensive discussion. A correlation among inflammation, hypertension, and cancer could accurately describe the clinical link between these diseases. In addition, dyshomeostasis of Ca2+ has been considered to be involved in both cancer and hypertension, and inflammation. There is a strong link between Ca2+ signalling, e.g. enhanced Ca2+ signals, and inflammatory outcomes. cAMP also modulates pro- and anti-inflammatory outcomes; pharmaceuticals, which increase intracellular cAMP levels, can decrease the production of proinflammatory mediators and enhance the production of antiinflammatory outcomes.

Objective: This article highlights the participation of Ca2+/cAMP signalling in the clinical association among inflammation, hypertension, and an enhanced risk for the development of cancer. In addition, considering that research on coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviews recent reports related to the role of Ca2+ channel blockers in restoring Ca2+ signalling disruption due to COVID-19, including the relationship among COVID-19, cancer, and hypertension.

Conclusion: An understanding of the association among these diseases could expand current pharmacotherapy, involving Ca2+ channel blockers and pharmaceuticals that facilitate a rise in cAMP levels.

Keywords: Cancer, hypertension, Ca2+/cAMP signaling, COVID-19, inflammation, dyshomeostasis.

Next »
Graphical Abstract

[1]
Stocks, T.; Van Hemelrijck, M.; Manjer, J.; Bjørge, T.; Ulmer, H.; Hallmans, G.; Lindkvist, B.; Selmer, R.; Nagel, G.; Tretli, S.; Concin, H.; Engeland, A.; Jonsson, H.; Stattin, P. Blood pressure and risk of cancer incidence and mortality in the metabolic syndrome and cancer project. Hypertension, 2012, 59(4), 802-810.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.189258] [PMID: 22353615]
[2]
Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature, 2002, 420(6917), 860-867.
[http://dx.doi.org/10.1038/nature01322] [PMID: 12490959]
[3]
De Miguel, C.; Rudemiller, N.P.; Abais, J.M.; Mattson, D.L. Inflammation and hypertension: New understandings and potential therapeutic targets. Curr. Hypertens. Rep., 2015, 17(1), 507.
[http://dx.doi.org/10.1007/s11906-014-0507-z] [PMID: 25432899]
[4]
Balkwill, F.; Mantovani, A. Inflammation and cancer: Back to Virchow? Lancet, 2001, 357(9255), 539-545.
[http://dx.doi.org/10.1016/S0140-6736(00)04046-0] [PMID: 11229684]
[5]
Büsselberg, D.; Florea, A.M. Targeting intracellular calcium signaling ([Ca2+]i) to overcome acquired multidrug resistance of cancer cells: A mini-overview. Cancers (Basel), 2017, 9(5), E48.
[http://dx.doi.org/10.3390/cancers9050048] [PMID: 28486397]
[6]
Parkash, J.; Asotra, K. Calcium wave signaling in cancer cells. Life Sci., 2010, 87(19-22), 587-595.
[http://dx.doi.org/10.1016/j.lfs.2010.09.013] [PMID: 20875431]
[7]
Miranda-Ferreira, R.; de Pascual, R.; de Diego, A.M.; Caricati-Neto, A.; Gandía, L.; Jurkiewicz, A.; García, A.G. Single-vesicle catecholamine release has greater quantal content and faster kinetics in chromaffin cells from hypertensive, as compared with normotensive, rats. J. Pharmacol. Exp. Ther., 2008, 324(2), 685-693.
[http://dx.doi.org/10.1124/jpet.107.128819] [PMID: 17962518]
[8]
Miranda-Ferreira, R.; de Pascual, R.; Caricati-Neto, A.; Gandía, L.; Jurkiewicz, A.; García, A.G. Role of the endoplasmic reticulum and mitochondria on quantal catecholamine release from chromaffin cells of control and hypertensive rats. J. Pharmacol. Exp. Ther., 2009, 329(1), 231-240.
[http://dx.doi.org/10.1124/jpet.108.147413] [PMID: 19131584]
[9]
Miranda-Ferreira, R.; de Pascual, R.; Smaili, S.S.; Caricati-Neto, A.; Gandía, L.; García, A.G.; Jurkiewicz, A. Greater cytosolic and mitochondrial calcium transients in adrenal medullary slices of hypertensive, compared with normotensive rats. Eur. J. Pharmacol., 2010, 636(1-3), 126-136.
[http://dx.doi.org/10.1016/j.ejphar.2010.03.044] [PMID: 20361955]
[10]
Bergantin, L.B.; Caricati-Neto, A. The “Calcium Paradox” and its Impact on Neurological and Psychiatric Diseases, 2nd ed; Cambridge Scholars Publishing: Newcastle upon Tyne, England, 2018.
[11]
Dalal, P.J.; Muller, W.A.; Sullivan, D.P. Endothelial cell calcium signaling during barrier function and inflammation. Am. J. Pathol., 2020, 190(3), 535-542.
[http://dx.doi.org/10.1016/j.ajpath.2019.11.004] [PMID: 31866349]
[12]
Monteith, G.R.; Davis, F.M.; Roberts-Thomson, S.J. Calcium channels and pumps in cancer: changes and consequences. J. Biol. Chem., 2012, 287(38), 31666-31673.
[http://dx.doi.org/10.1074/jbc.R112.343061] [PMID: 22822055]
[13]
Munaron, L.; Genova, T.; Avanzato, D.; Antoniotti, S.; Fiorio Pla, A. Targeting calcium channels to block tumor vascularization. Recent Patents Anticancer Drug Discov., 2013, 8(1), 27-37.
[http://dx.doi.org/10.2174/1574892811308010027] [PMID: 22530660]
[14]
Kim, K.H.; Kim, D.; Park, J.Y.; Jung, H.J.; Cho, Y.H.; Kim, H.K.; Han, J.; Choi, K.Y.; Kwon, H.J. NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. J. Mol. Med. (Berl.), 2015, 93(5), 499-509.
[http://dx.doi.org/10.1007/s00109-014-1235-1] [PMID: 25471482]
[15]
Yoshida, J.; Ishibashi, T.; Nishio, M. G1 cell cycle arrest by amlodipine, a dihydropyridine Ca2+ channel blocker, in human epidermoid carcinoma A431 cells. Biochem. Pharmacol., 2007, 73(7), 943-953.
[http://dx.doi.org/10.1016/j.bcp.2006.12.011] [PMID: 17217918]
[16]
Krouse, A.J.; Gray, L.; Macdonald, T.; McCray, J. Repurposing and rescuing of mibefradil, an antihypertensive, for cancer: A case study. Assay Drug Dev. Technol., 2015, 13(10), 650-653.
[http://dx.doi.org/10.1089/adt.2015.29014.ajkdrrr] [PMID: 26690767]
[17]
Bergantin, L.B. Diabetes and cancer: Debating the link through Ca2+/cAMP signalling. Cancer Lett., 2019, 448, 128-131.
[http://dx.doi.org/10.1016/j.canlet.2019.02.017] [PMID: 30771427]
[18]
Bergantin, L.B. Ca2+and cAMP: Do these intracellular messengers ‘work’ independently? of course not, and the history goes ahead..... J. Clin. Exp. Oncol., 2017, 7, 1.
[19]
Errante, P.R.; Menezes-Rodrigues, F.S.; Leite, A.A.; Caricati-Neto, A.; Bergantin, L.B. New antitumoral pharmacological strategies involving Ca2+/cAMP signaling pathways. J. Cancer Epidemiol. Prev., 2017, 2(1-3), 1-6.
[20]
Errante, P.R.; Caricati-Neto, A.; Bergantin, L.B. Insights for the inhibition of cancer progression: Revisiting Ca2+ and cAMP signalling pathways. Adv. Cancer Prev., 2017, 2(1), 1-2.
[http://dx.doi.org/10.4172/2472-0429.1000e103]
[21]
Errante, P.R.; Menezes-Rodrigues, F.S.; Caricati-Neto, A.; Bergantin, L.B. The pharmacological modulation of Ca2+/cAMP intracellular signaling pathways and traditional antitumoral pharmaceuticals: a plausible multitarget combined therapy? J. Clin. Exp. Oncol., 2017, 6(4), 1-3.
[http://dx.doi.org/10.4172/2324-9110.1000e111]
[22]
Errante, P.R.; Menezes-Rodrigues, F.S.; Leite, A.A.; Caricati-Neto, A.; Bergantin, L.B. The second messengers Ca2+ and cAMP as potential therapeutic targets for the control of cancer progression. Adv. Cancer Prev., 2017, 2(2), 1-2.
[http://dx.doi.org/10.4172/2472-0429.1000e105]
[23]
Murray, F.; Insel, P.A. Targeting cAMP in chronic lymphocytic leukemia: A pathway-dependent approach for the treatment of leukemia and lymphoma. Expert Opin. Ther. Targets, 2013, 17(8), 937-949.
[http://dx.doi.org/10.1517/14728222.2013.798304] [PMID: 23647244]
[24]
Raker, V.K.; Becker, C.; Steinbrink, K. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front. Immunol., 2016, 7, 123.
[http://dx.doi.org/10.3389/fimmu.2016.00123] [PMID: 27065076]
[25]
Moore, A.R.; Willoughby, D.A. The role of cAMP regulation in controlling inflammation. Clin. Exp. Immunol., 1995, 101(3), 387-389.
[http://dx.doi.org/10.1111/j.1365-2249.1995.tb03123.x] [PMID: 7664483]
[26]
Erdogan, S.; Aslantas, O.; Celik, S.; Atik, E. The effects of increased cAMP content on inflammation, oxidative stress and PDE4 transcripts during Brucella melitensis infection. Res. Vet. Sci., 2008, 84(1), 18-25.
[http://dx.doi.org/10.1016/j.rvsc.2007.02.003] [PMID: 17397885]
[27]
Tavares, L.P.; Negreiros-Lima, G.L.; Lima, K.M. E Silva, P.M.R.; Pinho, V.; Teixeira, M.M.; Sousa, L.P. Blame the signaling: Role of cAMP for the resolution of inflammation. Pharmacol. Res., 2020, 159, 105030.
[http://dx.doi.org/10.1016/j.phrs.2020.105030] [PMID: 32562817]
[28]
Stocks, T.; Borena, W.; Strohmaier, S.; Bjørge, T.; Manjer, J.; Engeland, A.; Johansen, D.; Selmer, R.; Hallmans, G.; Rapp, K.; Concin, H.; Jonsson, H.; Ulmer, H.; Stattin, P. Cohort profile: The metabolic syndrome and cancer project (Me-Can). Int. J. Epidemiol., 2010, 39(3), 660-667.
[http://dx.doi.org/10.1093/ije/dyp186] [PMID: 19380371]
[29]
Corrao, G.; Scotti, L.; Bagnardi, V.; Sega, R. Hypertension, antihypertensive therapy and renal-cell cancer: A meta-analysis. Curr. Drug Saf., 2007, 2(2), 125-133.
[http://dx.doi.org/10.2174/157488607780598296] [PMID: 18690958]
[30]
Andreotti, G.; Boffetta, P.; Rosenberg, P.S.; Berndt, S.I.; Karami, S.; Menashe, I.; Yeager, M.; Chanock, S.J.; Zaridze, D.; Matteev, V.; Janout, V.; Kollarova, H.; Bencko, V.; Navratilova, M.; Szeszenia-Dabrowska, N.; Mates, D.; Rothman, N.; Brennan, P.; Chow, W.H.; Moore, L.E. Variants in blood pressure genes and the risk of renal cell carcinoma. Carcinogenesis, 2010, 31(4), 614-620.
[http://dx.doi.org/10.1093/carcin/bgp321] [PMID: 20047954]
[31]
Seretis, A.; Cividini, S.; Markozannes, G.; Tseretopoulou, X.; Lopez, D.S.; Ntzani, E.E.; Tsilidis, K.K. Association between blood pressure and risk of cancer development: A systematic review and meta-analysis of observational studies. Sci. Rep., 2019, 9(1), 8565.
[http://dx.doi.org/10.1038/s41598-019-45014-4] [PMID: 31189941]
[32]
Zheng, A.; Peng, F.; Xu, B.; Zhao, J.; Liu, H.; Peng, J. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. J. Infect., 2020. S0163-4453-30234-6.
[33]
Yang, G.; Tan, Z.; Zhou, L.; Yang, M.; Peng, L.; Liu, J.; Cai, J.; Yang, R.; Han, J.; Huang, Y.; He, S. Effects of angiotensin II receptor blockers and ACE (angiotensin-converting enzyme) inhibitors on virus inhection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: A single-center retrospective study. Hypertension, 2020, 76(1), 51-58.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15143] [PMID: 32348166]
[34]
Barbaro, N.R.; Fontana, V.; Modolo, R.; De Faria, A.P.; Sabbatini, A.R.; Fonseca, F.H.; Anhê, G.F.; Moreno, H. Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers. Blood Press., 2015, 24(1), 7-13.
[http://dx.doi.org/10.3109/08037051.2014.940710] [PMID: 25061978]
[35]
Kow, C.S.; Ramachandram, D.S.; Hasan, S.S. Clinical outcomes of hypertensive patients with COVID-19 receiving calcium channel blockers: A systematic review and meta-analysis. Hypertens. Res., 2021, 1-4 Epub ahead of print
[http://dx.doi.org/10.1038/s41440-021-00786-z] [PMID: 34754084]
[36]
Passaro, A.; Bestvina, C.; Velez Velez, M.; Garassino, M.C.; Garon, E.; Peters, S. Severity of COVID-19 in patients with lung cancer: Evidence and challenges. J. Immunother. Cancer, 2021, 9(3), e002266.
[http://dx.doi.org/10.1136/jitc-2020-002266] [PMID: 33737345]
[37]
Saini, K.S.; Tagliamento, M.; Lambertini, M.; McNally, R.; Romano, M.; Leone, M.; Curigliano, G.; de Azambuja, E. Mortality in patients with cancer and coronavirus disease 2019: A systematic review and pooled analysis of 52 studies. Eur. J. Cancer, 2020, 139, 43-50.
[http://dx.doi.org/10.1016/j.ejca.2020.08.011] [PMID: 32971510]
[38]
Gomez-Ospina, N.; Tsuruta, F.; Barreto-Chang, O.; Hu, L.; Dolmetsch, R. The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell, 2006, 127(3), 591-606.
[http://dx.doi.org/10.1016/j.cell.2006.10.017] [PMID: 17081980]
[39]
Kale, V.P.; Amin, S.G.; Pandey, M.K. Targeting ion channels for cancer therapy by repurposing the approved drugs. Biochim. Biophys. Acta, 2015, 1848(10 Pt B), 2747-2755.
[http://dx.doi.org/10.1016/j.bbamem.2015.03.034] [PMID: 25843679]
[40]
Dziegielewska, B.; Gray, L.S.; Dziegielewski, J. T-type calcium channels blockers as new tools in cancer therapies. Pflugers Arch., 2014, 466(4), 801-810.
[http://dx.doi.org/10.1007/s00424-014-1444-z] [PMID: 24449277]
[41]
Gackière, F.; Bidaux, G.; Delcourt, P.; Van Coppenolle, F.; Katsogiannou, M.; Dewailly, E.; Bavencoffe, A.; Van Chuoï-Mariot, M.T.; Mauroy, B.; Prevarskaya, N.; Mariot, P. CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. J. Biol. Chem., 2008, 283(15), 10162-10173.
[http://dx.doi.org/10.1074/jbc.M707159200] [PMID: 18230611]
[42]
Latour, I.; Louw, D.F.; Beedle, A.M.; Hamid, J.; Sutherland, G.R.; Zamponi, G.W. Expression of T-type calcium channel splice variants in human glioma. Glia, 2004, 48(2), 112-119.
[http://dx.doi.org/10.1002/glia.20063] [PMID: 15378657]
[43]
Ohkubo, T.; Yamazaki, J. T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells. Int. J. Oncol., 2012, 41(1), 267-275.
[http://dx.doi.org/10.3892/ijo.2012.1422] [PMID: 22469755]
[44]
Bergantin, L.B.; Souza, C.F.; Ferreira, R.M.; Smaili, S.S.; Jurkiewicz, N.H.; Caricati-Neto, A.; Jurkiewicz, A. Novel model for “calcium paradox” in sympathetic transmission of smooth muscles: Role of cyclic AMP pathway. Cell Calcium, 2013, 54(3), 202-212.
[http://dx.doi.org/10.1016/j.ceca.2013.06.004] [PMID: 23849429]
[45]
Bergantin, L.B.; Caricati-Neto, A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction. Eur. J. Pharmacol., 2016, 788, 255-260.
[http://dx.doi.org/10.1016/j.ejphar.2016.06.034] [PMID: 27349146]
[46]
Bergantin, L.B. Neurodegenerative diseases: Where to go from now? Thought provoking through Ca2+/cAMP signaling interaction. Brain Disord. Ther., 2017, 6, e125.
[http://dx.doi.org/10.4172/2168-975X.1000e125]
[47]
Bergantin, L.B. Neurological disorders: Is there a horizon? Emerging ideas from the interaction between Ca2+ and camp signaling pathways. J. Neurol. Disord., 2017, 5, e124.
[http://dx.doi.org/10.4172/2329-6895.1000e124]
[48]
Caricati-Neto, A.; García, A.G.; Bergantin, L.B. Pharmacological implications of the Ca(2+)/cAMP signaling interaction: From risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol. Res. Perspect., 2015, 3(5), e00181.
[http://dx.doi.org/10.1002/prp2.181] [PMID: 26516591]
[49]
Bergantin, L.B. Common issues among asthma, epilepsy, and schizophrenia: From inflammation to Ca2+/cAMP signalling. Antiinflamm. Antiallergy Agents Med. Chem., 2020. Epub ahead of print
[http://dx.doi.org/10.2174/1871523019999201110192029] [PMID: 33176668]
[50]
Caricati-Neto, A.; Bergantin, L.B. Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer’s disease. J. Syst. Integr. Neurosci., 2017, 3
[http://dx.doi.org/10.15761/JSIN.1000185]
[51]
Caricati-Neto, A.; Bergantin, L.B. The passion of a scientific discovery: The “calcium paradox” due to Ca2+/camp interaction. J. Syst. Integr. Neurosci., 2017, 3
[http://dx.doi.org/10.15761/JSIN.1000186]
[52]
Caricati-Neto, A.; Bergantin, L.B. From a “eureka insight” to a novel potential therapeutic target to treat Parkinson’s disease: The Ca2+/camp signalling interaction. J. Syst. Integr. Neurosci., 2017, 4
[http://dx.doi.org/10.15761/JSIN.1000187]
[53]
Bergantin, L.B. The interactions between Alzheimer’s disease and major depression: Role of Ca2+ channel blockers and Ca2+/cAMP signalling. Curr. Drug Res. Rev., 2020, 12(2), 97-102. Epub ahead of print
[http://dx.doi.org/10.2174/2589977512666200217093356] [PMID: 32065096]
[54]
Bergantin, L.B. The complex link between schizophrenia and dementia: Targeting Ca2+/cAMP signalling. Curr. Pharm. Des., 2020, 26(27), 3326-3331.
[http://dx.doi.org/10.2174/1381612826666200318144521] [PMID: 32186273]
[55]
Bergantin, L.B. A link between brain insulin resistance and cognitive dysfunctions: Targeting Ca2+/cAMP signalling. Cent. Nerv. Syst. Agents Med. Chem., 2020, 20(2), 103-109.
[http://dx.doi.org/10.2174/1871524920666200129121232] [PMID: 31995022]
[56]
Bergantin, L.B. A hypothesis for the relationship between depression and cancer: Role of Ca2+/cAMP signalling. Anticancer. Agents Med. Chem., 2020, 20(7), 777-782.
[http://dx.doi.org/10.2174/1871520620666200220113817] [PMID: 32077833]
[57]
Kleppe, R.; Krakstad, C.; Selheim, F.; Kopperud, R.; Døskeland, S.O. The cAMP-dependent protein kinase pathway as therapeutic target: Possibilities and pitfalls. Curr. Top. Med. Chem., 2011, 11(11), 1393-1405.
[http://dx.doi.org/10.2174/156802611795589629] [PMID: 21513494]
[58]
Naviglio, S.; Caraglia, M.; Abbruzzese, A.; Chiosi, E.; Di Gesto, D.; Marra, M.; Romano, M.; Sorrentino, A.; Sorvillo, L.; Spina, A.; Illiano, G. Protein kinase A as a biological target in cancer therapy. Expert Opin. Ther. Targets, 2009, 13(1), 83-92.
[http://dx.doi.org/10.1517/14728220802602349] [PMID: 19063708]
[59]
Fajardo, A.M.; Piazza, G.A.; Tinsley, H.N. The role of cyclic nucleotide signaling pathways in cancer: Targets for prevention and treatment. Cancers (Basel), 2014, 6(1), 436-458.
[http://dx.doi.org/10.3390/cancers6010436] [PMID: 24577242]
[60]
Lerner, A.; Epstein, P.M. Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies. Biochem. J., 2006, 393(Pt 1), 21-41.
[http://dx.doi.org/10.1042/BJ20051368] [PMID: 16336197]
[61]
Chawla, R.K.; Shlaer, S.M.; Lawson, D.H.; Murray, T.G.; Schmidt, F.; Shoji, M.; Nixon, D.W.; Richmond, A.; Rudman, D. Elevated plasma and urinary guanosine 3′:5′-monophosphate and increased production rate in patients with neoplastic diseases. Cancer Res., 1980, 40(11), 3915-3920.
[PMID: 6258769]
[62]
Aleksijevic, A.; Lang, J.M.; Giron, C.; Stoclet, J.C.; Mayer, S.; Oberling, F. Alterations of peripheral blood lymphocyte cyclic AMP and cyclic GMP in untreated patients with hodgkin’s disease. Clin. Immunol. Immunopathol., 1983, 26(3), 398-405.
[http://dx.doi.org/10.1016/0090-1229(83)90124-1] [PMID: 6307567]
[63]
Tortorella, C.; Piazzolla, G.; Spaccavento, F.; Antonaci, S. Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis. Mediators Inflamm., 1998, 7(6), 391-396.
[http://dx.doi.org/10.1080/09629359890767] [PMID: 9927231]
[64]
García-Bermejo, L.; Pérez, C.; Vilaboa, N.E.; de Blas, E.; Aller, P. cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cells. J. Cell Sci., 1998, 111(Pt 5), 637-644.
[http://dx.doi.org/10.1242/jcs.111.5.637] [PMID: 9454737]
[65]
Monahan, T.M.; Marchand, N.W.; Fritz, R.R.; Abell, C.W. Cyclic adenosine 3′:5′-monophosphate levels and activities of related enzymes in normal and leukemic lymphocytes. Cancer Res., 1975, 35(9), 2540-2547.
[PMID: 167962]
[66]
Carpentieri, U.; Monahan, T.M.; Gustavson, L.P. Observations on the level of cyclic nucleotides in three population of human lymphocytes in culture. J. Cyclic Nucleotide Res., 1980, 6(4), 253-259.
[PMID: 6259221]
[67]
Lee, R.; Wolda, S.; Moon, E.; Esselstyn, J.; Hertel, C.; Lerner, A. PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP. Cell. Signal., 2002, 14(3), 277-284.
[http://dx.doi.org/10.1016/S0898-6568(01)00250-9] [PMID: 11812656]
[68]
Hanoune, J.; Defer, N. Regulation and role of adenylyl cyclase isoforms. Annu. Rev. Pharmacol. Toxicol., 2001, 41, 145-174.
[http://dx.doi.org/10.1146/annurev.pharmtox.41.1.145] [PMID: 11264454]
[69]
Briggs, C.A.; McAfee, D.A.; McCaman, R.E. Long-term regulation of synaptic acetylcholine release and nicotinic transmission: The role of cyclic AMP. Br. J. Pharmacol., 1988, 93(2), 399-411.
[http://dx.doi.org/10.1111/j.1476-5381.1988.tb11447.x] [PMID: 2833971]
[70]
Kuba, K.; Kumamoto, E. Long-term potentiation of transmitter release induced by adrenaline in bull-frog sympathetic ganglia. J. Physiol., 1986, 374, 515-530.
[http://dx.doi.org/10.1113/jphysiol.1986.sp016095] [PMID: 2427705]
[71]
Braas, K.M.; Rossignol, T.M.; Girard, B.M.; May, V.; Parsons, R.L. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) decreases neuronal somatostatin immunoreactivity in cultured guinea-pig parasympathetic cardiac ganglia. Neuroscience, 2004, 126(2), 335-346.
[http://dx.doi.org/10.1016/j.neuroscience.2004.04.007] [PMID: 15207351]
[72]
Chern, Y.J.; Kim, K.T.; Slakey, L.L.; Westhead, E.W. Adenosine receptors activate adenylate cyclase and enhance secretion from bovine adrenal chromaffin cells in the presence of forskolin. J. Neurochem., 1988, 50(5), 1484-1493.
[http://dx.doi.org/10.1111/j.1471-4159.1988.tb03034.x] [PMID: 2834514]
[73]
Doyle, M.E.; Egan, J.M. Pharmacological agents that directly modulate insulin secretion. Pharmacol. Rev., 2003, 55(1), 105-131.
[http://dx.doi.org/10.1124/pr.55.1.7] [PMID: 12615955]
[74]
von Ruden, L.; Neher, E. Ca-dependent early step in the release of catecholamines from adrenal chromaffin cells. Science, 1993, 262(5136), 1061-1065.
[http://dx.doi.org/10.1126/science.8235626]
[75]
Bittner, M.A.; Holz, R.W. Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components. J. Biol. Chem., 1992, 267(23), 16219-16225.
[http://dx.doi.org/10.1016/S0021-9258(18)41988-6] [PMID: 1644807]
[76]
Heinemann, C.; von Rüden, L.; Chow, R.H.; Neher, E. A two-step model of secretion control in neuroendocrine cells. Pflugers Arch., 1993, 424(2), 105-112.
[http://dx.doi.org/10.1007/BF00374600] [PMID: 8414901]
[77]
Prentki, M.; Matschinsky, F.M. Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol. Rev., 1987, 67(4), 1185-1248.
[http://dx.doi.org/10.1152/physrev.1987.67.4.1185] [PMID: 2825225]
[78]
Byrne, J.H.; Kandel, E.R. Presynaptic facilitation revisited: State and time dependence. J. Neurosci., 1996, 16(2), 425-435.
[http://dx.doi.org/10.1523/JNEUROSCI.16-02-00425.1996] [PMID: 8551327]
[79]
Kits, K.S.; Mansvelder, H.D. Regulation of exocytosis in neuroendocrine cells: Spatial organization of channels and vesicles, stimulus-secretion coupling, calcium buffers and modulation. Brain Res., 2000, 33(1), 78-94.
[http://dx.doi.org/10.1016/S0165-0173(00)00023-0] [PMID: 10967354]
[80]
Muto, Y.; Nagao, T.; Yamada, M.; Mikoshiba, K.; Urushidani, T. A proposed mechanism for the potentiation of cAMP-mediated acid secretion by carbachol. Am. J. Physiol. Cell Physiol., 2001, 280(1), C155-C165.
[http://dx.doi.org/10.1152/ajpcell.2001.280.1.C155] [PMID: 11121387]
[81]
Sakaba, T.; Neher, E. Preferential potentiation of fast-releasing synaptic vesicles by cAMP at the calyx of Held. Proc. Natl. Acad. Sci. USA, 2001, 98(1), 331-336.
[http://dx.doi.org/10.1073/pnas.98.1.331] [PMID: 11134533]
[82]
Sato, K.; Ohsaga, A.; Oshiro, T.; Ito, S.; Maruyama, Y. Involvement of GTP-binding protein in pancreatic cAMP-mediated exocytosis. Pflugers Arch., 2002, 443(3), 394-398.
[http://dx.doi.org/10.1007/s004240100711] [PMID: 11810208]
[83]
Trudeau, L.E.; Fang, Y.; Haydon, P.G. Modulation of an early step in the secretory machinery in hippocampal nerve terminals. Proc. Natl. Acad. Sci. USA, 1998, 95(12), 7163-7168.
[http://dx.doi.org/10.1073/pnas.95.12.7163] [PMID: 9618556]
[84]
Trudeau, L.E.; Emery, D.G.; Haydon, P.G. Direct modulation of the secretory machinery underlies PKA-dependent synaptic facilitation in hippocampal neurons. Neuron, 1996, 17(4), 789-797.
[http://dx.doi.org/10.1016/S0896-6273(00)80210-X] [PMID: 8893035]
[85]
Weisskopf, M.G.; Castillo, P.E.; Zalutsky, R.A.; Nicoll, R.A. Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science, 1994, 265(5180), 1878-1882.
[http://dx.doi.org/10.1126/science.7916482]
[86]
Chen, C.; Regehr, W.G. The mechanism of cAMP-mediated enhancement at a cerebellar synapse. J. Neurosci., 1997, 17(22), 8687-8694.
[http://dx.doi.org/10.1523/JNEUROSCI.17-22-08687.1997] [PMID: 9348337]
[87]
Salin, P.A.; Malenka, R.C.; Nicoll, R.A. Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron, 1996, 16(4), 797-803.
[http://dx.doi.org/10.1016/S0896-6273(00)80099-9] [PMID: 8607997]
[88]
Zhong, N.; Zucker, R.S. Roles of Ca2+, hyperpolarization and cyclic nucleotide-activated channel activation, and actin in temporal synaptic tagging. J. Neurosci., 2004, 24(17), 4205-4212.
[http://dx.doi.org/10.1523/JNEUROSCI.0111-04.2004] [PMID: 15115816]
[89]
Shuster, M.J.; Camardo, J.S.; Siegelbaum, S.A.; Kandel, E.R. Cyclic AMP-dependent protein kinase closes the serotonin-sensitive K+ channels of Aplysia sensory neurones in cell-free membrane patches. Nature, 1985, 313(6001), 392-395.
[http://dx.doi.org/10.1038/313392a0] [PMID: 2578623]
[90]
Yoshihara, M.; Suzuki, K.; Kidokoro, Y. Two independent pathways mediated by cAMP and protein kinase A enhance spontaneous transmitter release at Drosophila neuromuscular junctions. J. Neurosci., 2000, 20(22), 8315-8322.
[http://dx.doi.org/10.1523/JNEUROSCI.20-22-08315.2000] [PMID: 11069938]
[91]
Henquin, J.C. The interplay between cyclic AMP and ions in the stimulus-secretion coupling in pancreatic B-cells. Arch. Int. Physiol. Biochim., 1985, 93(1), 37-48.
[http://dx.doi.org/10.3109/13813458509104514] [PMID: 2409943]
[92]
Gromada, J.; Bokvist, K.; Ding, W.G.; Barg, S.; Buschard, K.; Renström, E.; Rorsman, P. Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J. Gen. Physiol., 1997, 110(3), 217-228.
[http://dx.doi.org/10.1085/jgp.110.3.217] [PMID: 9276750]
[93]
Won, J.G.; Orth, D.N. Roles of intracellular and extracellular calcium in the kinetic profile of adrenocorticotropin secretion by perifused rat anterior pituitary cells. I. Corticotropin-releasing factor stimulation. Endocrinology, 1990, 126(2), 849-857.
[http://dx.doi.org/10.1210/endo-126-2-849] [PMID: 2153529]
[94]
Quissell, D.O.; Barzen, K.A.; Deisher, L.M. Rat submandibular and parotid protein phosphorylation and exocytosis: effect of site-selective cAMP analogs. Crit. Rev. Oral Biol. Med., 1993, 4(3-4), 443-448.
[http://dx.doi.org/10.1177/10454411930040032601] [PMID: 7690603]
[95]
Kaupp, U.B.; Seifert, R. Cyclic nucleotide-gated ion channels. Physiol. Rev., 2002, 82(3), 769-824.
[http://dx.doi.org/10.1152/physrev.00008.2002] [PMID: 12087135]
[96]
Biel, M.; Schneider, A.; Wahl, C. Cardiac HCN channels: Structure, function, and modulation. Trends Cardiovasc. Med., 2002, 12(5), 206-212.
[http://dx.doi.org/10.1016/S1050-1738(02)00162-7] [PMID: 12161074]
[97]
Springett, G.M.; Kawasaki, H.; Spriggs, D.R. Non-kinase second-messenger signaling: New pathways with new promise. BioEssays, 2004, 26(7), 730-738.
[http://dx.doi.org/10.1002/bies.20057] [PMID: 15221855]
[98]
Halls, M.L.; Cooper, D.M. Regulation by Ca2+-signaling pathways of adenylyl cyclases. Cold Spring Harb. Perspect. Biol., 2011, 3(1), a004143.
[http://dx.doi.org/10.1101/cshperspect.a004143] [PMID: 21123395]
[99]
Antoni, F.A. Interactions between intracellular free Ca2+ and cyclic AMP in neuroendocrine cells. Cell Calcium, 2012, 51(3-4), 260-266.
[http://dx.doi.org/10.1016/j.ceca.2011.12.013] [PMID: 22385836]
[100]
Willoughby, D. Organization of cAMP signalling microdomains for optimal regulation by Ca2+ entry. Biochem. Soc. Trans., 2012, 40(1), 246-250.
[http://dx.doi.org/10.1042/BST20110613] [PMID: 22260699]
[101]
Fagan, K.A.; Graf, R.A.; Tolman, S.; Schaack, J.; Cooper, D.M. Regulation of a Ca2+-sensitive adenylyl cyclase in an excitable cell. Role of voltage-gated versus capacitative Ca2+ entry. J. Biol. Chem., 2000, 275(51), 40187-40194.
[http://dx.doi.org/10.1074/jbc.M006606200] [PMID: 11010970]
[102]
Goraya, T.A.; Masada, N.; Ciruela, A.; Willoughby, D.; Clynes, M.A.; Cooper, D.M. Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+. Cell. Signal., 2008, 20(2), 359-374.
[http://dx.doi.org/10.1016/j.cellsig.2007.10.024] [PMID: 18335582]
[103]
Giovannucci, D.R.; Groblewski, G.E.; Sneyd, J.; Yule, D.I. Targeted phosphorylation of inositol 1,4,5-trisphosphate receptors selectively inhibits localized Ca2+ release and shapes oscillatory Ca2+ signals. J. Biol. Chem., 2000, 275(43), 33704-33711.
[http://dx.doi.org/10.1074/jbc.M004278200] [PMID: 10887192]
[104]
Fechner, L.; Baumann, O.; Walz, B. Activation of the cyclic AMP pathway promotes serotonin-induced Ca2+ oscillations in salivary glands of the blowfly Calliphora vicina. Cell Calcium, 2013, 53(2), 94-101.
[http://dx.doi.org/10.1016/j.ceca.2012.10.004] [PMID: 23131569]
[105]
Chatton, J.Y.; Cao, Y.; Liu, H.; Stucki, J.W. Permissive role of cAMP in the oscillatory Ca2+ response to inositol 1,4,5-trisphosphate in rat hepatocytes. Biochem. J., 1998, 330(Pt 3), 1411-1416.
[http://dx.doi.org/10.1042/bj3301411] [PMID: 9494114]
[106]
Lee, R.J.; Foskett, J.K. cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways. J. Clin. Invest., 2010, 120(9), 3137-3148.
[http://dx.doi.org/10.1172/JCI42992] [PMID: 20739756]
[107]
Marks, A.R. Calcium cycling proteins and heart failure: Mechanisms and therapeutics. J. Clin. Invest., 2013, 123(1), 46-52.
[http://dx.doi.org/10.1172/JCI62834] [PMID: 23281409]
[108]
Zhang, L.K.; Sun, Y.; Zeng, H.; Wang, Q.; Jiang, X.; Shang, W.J.; Wu, Y.; Li, S.; Zhang, Y.L.; Hao, Z.N.; Chen, H.; Jin, R.; Liu, W.; Li, H.; Peng, K.; Xiao, G. Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension. Cell Discov., 2020, 6(1), 96.
[http://dx.doi.org/10.1038/s41421-020-00235-0] [PMID: 33349633]
[109]
Bergantin, L.B. Diabetes and inflammatory diseases: An overview from the perspective of Ca2+/3′-5′-cyclic adenosine monophosphate signaling. World J. Diabetes, 2021, 12(6), 767-779.
[http://dx.doi.org/10.4239/wjd.v12.i6.767] [PMID: 34168726]
[110]
Olivier, M. Modulation of host cell intracellular Ca2+. Parasitol. Today, 1996, 12(4), 145-150.
[http://dx.doi.org/10.1016/0169-4758(96)10006-5] [PMID: 15275223]
[111]
Scherbik, S.V.; Brinton, M.A. Virus-induced Ca2+ influx extends survival of West Nile virus-infected cells. J. Virol., 2010, 84(17), 8721-8731.
[http://dx.doi.org/10.1128/JVI.00144-10] [PMID: 20538858]
[112]
Dionicio, C.L.; Peña, F.; Constantino-Jonapa, L.A.; Vazquez, C.; Yocupicio-Monroy, M.; Rosales, R.; Zambrano, J.L.; Ruiz, M.C.; Del Angel, R.M.; Ludert, J.E. Dengue virus induced changes in Ca2+ homeostasis in human hepatic cells that favor the viral replicative cycle. Virus Res., 2018, 245, 17-28.
[http://dx.doi.org/10.1016/j.virusres.2017.11.029] [PMID: 29269104]
[113]
Nugent, K.M.; Shanley, J.D. Verapamil inhibits influenza A virus replication. Arch. Virol., 1984, 81(1-2), 163-170.
[http://dx.doi.org/10.1007/BF01309305] [PMID: 6743023]
[114]
Johansen, L.M.; DeWald, L.E.; Shoemaker, C.J.; Hoffstrom, B.G.; Lear-Rooney, C.M.; Stossel, A.; Nelson, E.; Delos, S.E.; Simmons, J.A.; Grenier, J.M.; Pierce, L.T.; Pajouhesh, H.; Lehár, J.; Hensley, L.E.; Glass, P.J.; White, J.M.; Olinger, G.G. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci. Transl. Med., 2015, 7(290), 290ra89.
[http://dx.doi.org/10.1126/scitranslmed.aaa5597] [PMID: 26041706]
[115]
D’Elia, J.A.; Weinrauch, L.A. Calcium ion channels: Roles in infection and sepsis mechanisms of calcium channel blocker benefits in immunocompromised patients at risk for infection. Int. J. Mol. Sci., 2018, 19(9), 19.
[http://dx.doi.org/10.3390/ijms19092465] [PMID: 30134544]
[116]
Bergantin, L.B. Cancer and hypertension: Debating the clinical link through the Ca2+/cAMP signaling. Glob. Vaccines Immunol., 2018, 3
[http://dx.doi.org/10.15761/GVI.1000131]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version613msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[04:42:15] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[04:42:16] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[04:42:16] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[04:42:16] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (162ms)time
  • Application (451ms)time
  • 1 x Application (73.63%)
    451ms
    1 x Booting (26.36%)
    162ms
    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 duplicated312ms
    • 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 ('59780576','',1,1740458535,1740458535) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740458535
      6.35msalphaeurekaselec_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 ('59780576','/article/120904',1,1740458535,1740458535)
      270μsalphaeurekaselec_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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) 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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) 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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) 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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) 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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) 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 >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59780576 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59780576) limit 1
      27.78msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59780576
      • 1: 59780576
      • 2: 59780576
      • 3: 59780576
      • 4: 59780576
      • 5: 59780576
      • 6: 59780576
      • 7: 59780576
      • 8: 59780576
      • 9: 59780576
      • 10: 59780576
      • 11: 59780576
      • 12: 59780576
      • 13: 59780576
      • 14: 59780576
      • 15: 59780576
      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=120904
      1.18msalphaeurekaselec_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` = 7 limit 1
      4.16msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 7
      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=7) and sj.journal_id!=7 group by `j`.`nid`) as `aggregate_table`
      1.58msalphaeurekaselec_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=7) and sj.journal_id!=7 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      14.24msalphaeurekaselec_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=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.38msalphaeurekaselec_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=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.22msalphaeurekaselec_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` = '120904'
      27.66msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 120904
      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` = '120904'
      30msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 120904
      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` = '120904' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      7.21msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 120904
      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
      410μsalphaeurekaselec_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
      740μsalphaeurekaselec_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 = 7 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      73.41msalphaeurekaselec_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 = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      32.41msalphaeurekaselec_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 = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      23.36msalphaeurekaselec_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` = 120904 limit 1
      3.32msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 120904
      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 = 120904 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` = 201151 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 201151
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      310μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CCDT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      390μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CCDT
      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 = '120904' 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) )
      14.95msalphaeurekaselec_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 = '11627' 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) )
      480μsalphaeurekaselec_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 = '3273' 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3273) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3273) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3273)
      23.7msalphaeurekaselec_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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11627) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11627) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11627)
      940μsalphaeurekaselec_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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 120904) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 120904) 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 <= 59780576 and j.to_ip >=59780576 )) and ((j.from_date <= 1740458536 and j.to_date >= 1740458536 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 120904)
      1.02msalphaeurekaselec_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` < '351' and is_uploaded = 1 and issue_id = 11627 order by cast(first_page as SIGNED) desc limit 1
      650μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 351
      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` > '360' and is_uploaded = 1 and issue_id = 11627 order by cast(first_page as SIGNED) asc limit 1
      630μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 360
      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'
      190μsalphaeurekaselec_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
      290μsalphaeurekaselec_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` = 120904 limit 1
      3.72msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 120904
      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` = 7 and `b`.`banner_from_date` <= 1740458536 and `b`.`banner_to_date` >= 1740458536 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      2.92msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740458536
      • 4: 1740458536
      • 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` = 7 and `b`.`banner_from_date` <= 1740458536 and `b`.`banner_to_date` >= 1740458536 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.62msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1740458536
      • 4: 1740458536
      • 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='990cba2499957ec94fc25148bac30b66'
      310μsalphaeurekaselec_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#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
        _token
        OQvfXI55PQ641OubxCK6EkfS2H5eQeq8zZqz2F1B
        uc_cart_id
        990cba2499957ec94fc25148bac30b66
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/120904" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/120904
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 04:42:16 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImErTDJJN1U2OW45UmFIV1lmbHFIZUE9PSIsInZhbHVlIjoibHBSZ0RLY09TSEVJM09KQmlreGpNYklYOHdnekJ2dVJicnNHeldzNlc2TUFnY2x0VkZybVkwa1hBM251ZDlRaFJCSmNDcUpKeFNSUEROcHRKbFdEZWFFWE1lWTBWYWdqQzdEcWs2VTVoMWhVb2k2a0ZScnVNVjN6UVNqSTQ5VzIiLCJtYWMiOiI2ZjM3NjQ0MWU4ZmRiMTMwMWUzZGZhZjkwYTM4ODY5NWMzM2JjZDFjY2IxYjI5NGI3MDYzZjgwNDc4MTViMmQwIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 16:42:16 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImErTDJJN1U2OW45UmFIV1lmbHFIZUE9PSIsInZhbHVlIjoibHBSZ0RLY09TSEVJM09KQmlreGpNYklYOHdnekJ2dVJicnNHeldzNlc2TUFnY2x0VkZybVkwa1hBM251ZDlRaFJCSmNDc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IllXQWxUNW5uVXFKZVozNmJhR3NQSXc9PSIsInZhbHVlIjoic2xKZk05bFdqazRDOU1JelpObTBQam1GVk80TXRXd1RYbnFjSHpDU1RZWU1pR0dGak1hOHRxN1pMUElHS2NwZ3o5NmpKQmwvZXRoTy9pNzIyelkwaUlSSlFEb25TRmlGaVhZdGdCT1k2WnIvdDIxcTcwQkx0bk9hUHhGV2JmN2QiLCJtYWMiOiIyNTc4NjgwOTdjY2MzMTE2NGVhNGQ5ZTU4NzMwY2YwZmY1ODUzNzgzMmFkZjAyZDE4ZTllMWRmMGIxOGFhMWM5IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IllXQWxUNW5uVXFKZVozNmJhR3NQSXc9PSIsInZhbHVlIjoic2xKZk05bFdqazRDOU1JelpObTBQam1GVk80TXRXd1RYbnFjSHpDU1RZWU1pR0dGak1hOHRxN1p" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImErTDJJN1U2OW45UmFIV1lmbHFIZUE9PSIsInZhbHVlIjoibHBSZ0RLY09TSEVJM09KQmlreGpNYklYOHdnekJ2dVJicnNHeldzNlc2TUFnY2x0VkZybVkwa1hBM251ZDlRaFJCSmNDcUpKeFNSUEROcHRKbFdEZWFFWE1lWTBWYWdqQzdEcWs2VTVoMWhVb2k2a0ZScnVNVjN6UVNqSTQ5VzIiLCJtYWMiOiI2ZjM3NjQ0MWU4ZmRiMTMwMWUzZGZhZjkwYTM4ODY5NWMzM2JjZDFjY2IxYjI5NGI3MDYzZjgwNDc4MTViMmQwIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 16:42:16 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImErTDJJN1U2OW45UmFIV1lmbHFIZUE9PSIsInZhbHVlIjoibHBSZ0RLY09TSEVJM09KQmlreGpNYklYOHdnekJ2dVJicnNHeldzNlc2TUFnY2x0VkZybVkwa1hBM251ZDlRaFJCSmNDc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IllXQWxUNW5uVXFKZVozNmJhR3NQSXc9PSIsInZhbHVlIjoic2xKZk05bFdqazRDOU1JelpObTBQam1GVk80TXRXd1RYbnFjSHpDU1RZWU1pR0dGak1hOHRxN1pMUElHS2NwZ3o5NmpKQmwvZXRoTy9pNzIyelkwaUlSSlFEb25TRmlGaVhZdGdCT1k2WnIvdDIxcTcwQkx0bk9hUHhGV2JmN2QiLCJtYWMiOiIyNTc4NjgwOTdjY2MzMTE2NGVhNGQ5ZTU4NzMwY2YwZmY1ODUzNzgzMmFkZjAyZDE4ZTllMWRmMGIxOGFhMWM5IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IllXQWxUNW5uVXFKZVozNmJhR3NQSXc9PSIsInZhbHVlIjoic2xKZk05bFdqazRDOU1JelpObTBQam1GVk80TXRXd1RYbnFjSHpDU1RZWU1pR0dGak1hOHRxN1p" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "OQvfXI55PQ641OubxCK6EkfS2H5eQeq8zZqz2F1B" "uc_cart_id" => "990cba2499957ec94fc25148bac30b66" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/120904" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 04:42:16GET/article/120904414362