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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Small Molecule Inhibitors against the Bacterial Pathogen Brucella

Author(s): Yingnan Wu, Ye Guo, Yuheng Ma, Hui Yu* and Zhanli Wang*

Volume 31, Issue 27, 2024

Published on: 28 September, 2023

Page: [4267 - 4285] Pages: 19

DOI: 10.2174/0929867331666230915153910

Price: $65

Abstract

Brucellosis remains one of the major zoonotic diseases worldwide. As a causative agent of brucellosis, it has many ways to evade recognition by the immune system, allowing it to replicate and multiply in the host, causing significant harm to both humans and animals. The pathogenic mechanism of Brucella has not been elucidated, making the identification of drug targets from the pathogenic mechanism a challenge. Metalloenzymatic targets and some protein targets unique to Brucella are exploitable in the development of inhibitors against this disease. The development of specific small molecule inhibitors is urgently needed for brucellosis treatment due to the antibiotic resistance of Brucella. This review summarizes the research on small molecule inhibitors of Brucella, which could be instructive for subsequent studies.

[1]
Boschiroli, M.L.; Foulongne, V.; O’Callaghan, D. Brucellosis: A worldwide zoonosis. Curr. Opin. Microbiol., 2001, 4(1), 58-64.
[http://dx.doi.org/10.1016/S1369-5274(00)00165-X] [PMID: 11173035]
[2]
Kirk, M.D.; Pires, S.M.; Black, R.E.; Caipo, M.; Crump, J.A.; Devleesschauwer, B.; Döpfer, D.; Fazil, A.; Fischer-Walker, C.L.; Hald, T.; Hall, A.J.; Keddy, K.H.; Lake, R.J.; Lanata, C.F.; Torgerson, P.R.; Havelaar, A.H.; Angulo, F.J. World Health Organization estimates of the global and regional disease burden of 22 foodborne bacterial, protozoal, and viral diseases, 2010: A data synthesis. PLoS Med., 2015, 12(12), e1001921.
[http://dx.doi.org/10.1371/journal.pmed.1001921] [PMID: 26633831]
[3]
Atluri, V.L.; Xavier, M.N.; de Jong, M.F.; den Hartigh, A.B.; Tsolis, R.M. Interactions of the human pathogenic Brucella species with their hosts. Annu. Rev. Microbiol., 2011, 65(1), 523-541.
[http://dx.doi.org/10.1146/annurev-micro-090110-102905] [PMID: 21939378]
[4]
Yu, D.; Hui, Y.; Zai, X.; Xu, J.; Liang, L.; Wang, B.; Yue, J.; Li, S. Comparative genomic analysis of Brucella abortus vaccine strain 104M reveals a set of candidate genes associated with its virulence attenuation. Virulence, 2015, 6(8), 745-754.
[http://dx.doi.org/10.1080/21505594.2015.1038015] [PMID: 26039674]
[5]
Jamil, T.; Melzer, F.; Saqib, M.; Shahzad, A.; Khan Kasi, K.; Hammad Hussain, M.; Rashid, I.; Tahir, U.; Khan, I.; Haleem Tayyab, M.; Ullah, S.; Mohsin, M.; Mansoor, M.K.; Schwarz, S.; Neubauer, H. Serological and molecular detection of bovine brucellosis at institutional livestock farms in Punjab, Pakistan. Int. J. Environ. Res. Public Health, 2020, 17(4), 1412.
[http://dx.doi.org/10.3390/ijerph17041412] [PMID: 32098207]
[6]
Hassan, H.; Salami, A.; Nehme, N.; Hakeem, R.; El Hage, J.; Awada, R. In prevalence and prevention of brucellosis in cattle in Lebanon. Vet. World, 2020, 13(2), 364-371.
[7]
Liu, Z.; Shen, T.; Wei, D.; Yu, Y.; Huang, D.; Guan, P. Analysis of the epidemiological, clinical characteristics, treatment and prognosis of human brucellosis during 2014–2018 in Huludao, China. Infect. Drug Resist., 2020, 13, 435-445.
[http://dx.doi.org/10.2147/IDR.S236326] [PMID: 32104015]
[8]
Njenga, M.K.; Ogolla, E.; Thumbi, S.M.; Ngere, I.; Omulo, S.; Muturi, M.; Marwanga, D.; Bitek, A.; Bett, B.; Widdowson, M.A.; Munyua, P.; Osoro, E.M. Comparison of knowledge, attitude, and practices of animal and human brucellosis between nomadic pastoralists and non-pastoralists in Kenya. BMC Public Health, 2020, 20(1), 269.
[http://dx.doi.org/10.1186/s12889-020-8362-0] [PMID: 32093689]
[9]
Khan, A.U.; Melzer, F.; El-Soally, S.A.G.E.; Elschner, M.C.; Mohamed, S.A.; Sayed Ahmed, M.A.; Roesler, U.; Neubauer, H.; El-Adawy, H. Serological and molecular identification of Brucella spp. in pigs from Cairo and Giza Governorates, Egypt. Pathogens, 2019, 8(4), 248.
[http://dx.doi.org/10.3390/pathogens8040248] [PMID: 31756893]
[10]
Ezama, A.; Gonzalez, J.P.; Majalija, S.; Bajunirwe, F. Assessing short evolution brucellosis in a highly Brucella endemic cattle keeping population of Western Uganda: a complementary use of Rose Bengal test and IgM rapid diagnostic test. BMC Public Health, 2018, 18(1), 315.
[http://dx.doi.org/10.1186/s12889-018-5228-9] [PMID: 29506522]
[11]
Zhang, X.W.; Ren, P.; Huang, T.L. Treatment of severe refractory thrombocytopenia in brucellosis with eltrombopag: A case report. Pediatr. Infect. Dis. J., 2022, 41(8), e332-e335.
[http://dx.doi.org/10.1097/INF.0000000000003555] [PMID: 35421043]
[12]
Perkins, S.D.; Smither, S.J.; Atkins, H.S. Towards a Brucella vaccine for humans. FEMS Microbiol. Rev., 2010, 34(3), 379-394.
[http://dx.doi.org/10.1111/j.1574-6976.2010.00211.x] [PMID: 20180858]
[13]
Głowacka, P.; Żakowska, D.; Naylor, K.; Niemcewicz, M.; Bielawska-Drózd, A. Brucella–virulence factors, pathogenesis and treatment. Pol. J. Microbiol., 2018, 67(2), 151-161.
[http://dx.doi.org/10.21307/pjm-2018-029] [PMID: 30015453]
[14]
Whatmore, A.M.; Perrett, L.L.; MacMillan, A.P. Characterisation of the genetic diversity of Brucella by multilocus sequencing. BMC Microbiol., 2007, 7(1), 34.
[http://dx.doi.org/10.1186/1471-2180-7-34] [PMID: 17448232]
[15]
Corbel, M. Brucellosis: An overview. Emerg. Infect. Dis., 1997, 3(2), 213-221.
[http://dx.doi.org/10.3201/eid0302.970219] [PMID: 9204307]
[16]
Hisham, Y.; Ashhab, Y. Identification of cross-protective potential antigens against pathogenic Brucella spp. through combining pan-genome analysis with reverse vaccinology. J. Immunol. Res., 2018.
[17]
Ewalt, D.R.; Payeur, J.B.; Martin, B.M.; Cummins, D.R.; Miller, W.G. Characteristics of a Brucella species from a bottlenose dolphin (Tursiops truncatus). J. Vet. Diagn. Invest., 1994, 6(4), 448-452.
[http://dx.doi.org/10.1177/104063879400600408] [PMID: 7858024]
[18]
Ross, H.; Foster, G.; Reid, R.; Jahans, K.; MacMillan, A. Brucella species infection in sea-mammals. Vet. Rec., 1994, 134(14), 359.
[http://dx.doi.org/10.1136/vr.134.14.359-b] [PMID: 8017020]
[19]
Martirosyan, A.; Moreno, E.; Gorvel, J.P. An evolutionary strategy for a stealthy intracellular Brucella pathogen. Immunol. Rev., 2011, 240(1), 211-234.
[http://dx.doi.org/10.1111/j.1600-065X.2010.00982.x] [PMID: 21349096]
[20]
Grilló, M.J.; Blasco, J.M.; Gorvel, J.P.; Moriyón, I.; Moreno, E. What have we learned from brucellosis in the mouse model? Vet. Res., 2012, 43(1), 29.
[http://dx.doi.org/10.1186/1297-9716-43-29] [PMID: 22500859]
[21]
Martirosyan, A.; Gorvel, J.P. Brucella evasion of adaptive immunity. Future Microbiol., 2013, 8(2), 147-154.
[http://dx.doi.org/10.2217/fmb.12.140] [PMID: 23374122]
[22]
Jansen, W.; Demars, A.; Nicaise, C.; Godfroid, J.; de Bolle, X.; Reboul, A.; Al Dahouk, S. Shedding of Brucella melitensis happens through milk macrophages in the murine model of infection. Sci. Rep., 2020, 10(1), 9421.
[http://dx.doi.org/10.1038/s41598-020-65760-0] [PMID: 32523093]
[23]
Ma, Z.; Li, R.; Hu, R.; Deng, X.; Xu, Y.; Zheng, W.; Yi, J.; Wang, Y.; Chen, C. Brucella abortus BspJ is a nucleomodulin that inhibits macrophage apoptosis and promotes intracellular survival of Brucella. Front. Microbiol., 2020, 11, 599205.
[http://dx.doi.org/10.3389/fmicb.2020.599205] [PMID: 33281799]
[24]
Hop, H.T.; Reyes, A.W.B.; Huy, T.X.N.; Arayan, L.T.; Min, W.; Lee, H.J.; Rhee, M.H.; Chang, H.H.; Kim, S. Activation of NF-kB-Mediated TNF-Induced antimicrobial immunity is required for the efficient Brucella abortus clearance in RAW 264.7 Cells. Front. Cell. Infect. Microbiol., 2017, 7, 437.
[http://dx.doi.org/10.3389/fcimb.2017.00437] [PMID: 29062811]
[25]
Boschiroli, M.L.; Ouahrani-Bettache, S.; Foulongne, V.; Michaux-Charachon, S.; Bourg, G.; Allardet-Servent, A.; Cazevieille, C.; Liautard, J.P.; Ramuz, M.; O’Callaghan, D. The Brucella suis virB operon is induced intracellularly in macrophages. Proc. Natl. Acad. Sci. USA, 2002, 99(3), 1544-1549.
[http://dx.doi.org/10.1073/pnas.032514299] [PMID: 11830669]
[26]
Celli, J.; de Chastellier, C.; Franchini, D.M.; Pizarro-Cerda, J.; Moreno, E.; Gorvel, J.P. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J. Exp. Med., 2003, 198(4), 545-556.
[http://dx.doi.org/10.1084/jem.20030088] [PMID: 12925673]
[27]
Starr, T.; Ng, T.W.; Wehrly, T.D.; Knodler, L.A.; Celli, J. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic, 2008, 9(5), 678-694.
[http://dx.doi.org/10.1111/j.1600-0854.2008.00718.x] [PMID: 18266913]
[28]
Roux, C.M.; Rolán, H.G.; Santos, R.L.; Beremand, P.D.; Thomas, T.L.; Adams, L.G.; Tsolis, R.M. Brucella requires a functional Type IV secretion system to elicit innate immune responses in mice. Cell. Microbiol., 2007, 9(7), 1851-1869.
[http://dx.doi.org/10.1111/j.1462-5822.2007.00922.x] [PMID: 17441987]
[29]
Ahmed, W.; Zheng, K.; Liu, Z.F. Establishment of chronic infection: Brucella’s stealth strategy. Front. Cell. Infect. Microbiol., 2016, 6, 30.
[http://dx.doi.org/10.3389/fcimb.2016.00030] [PMID: 27014640]
[30]
Pappas, G.; Akritidis, N.; Tsianos, E. Effective treatments in the management of brucellosis. Expert Opin. Pharmacother., 2005, 6(2), 201-209.
[http://dx.doi.org/10.1517/14656566.6.2.201] [PMID: 15757417]
[31]
Leite, D.M.C.; Brochet, X.; Resch, G.; Que, Y.A.; Neves, A.; Peña-Reyes, C. Computational prediction of inter-species relationships through omics data analysis and machine learning. BMC Bioinformatics, 2018, 19(S14)(Suppl. 14), 420.
[http://dx.doi.org/10.1186/s12859-018-2388-7] [PMID: 30453987]
[32]
Spink, W.W. Current status of therapy of brucellosis in human beings. J. Am. Med. Assoc., 1960, 172(7), 697-698.
[http://dx.doi.org/10.1001/jama.1960.63020070004016] [PMID: 13833372]
[33]
Xie, Q.; Zhang, X.; Cui, W.; Pang, Y. Construction of a nomogram for identifying refractory Mycoplasma pneumoniae pneumonia among macrolide-unresponsive Mycoplasma pneumoniae pneumonia in children. J. Inflamm. Res., 2022, 15, 6495-6504.
[http://dx.doi.org/10.2147/JIR.S387809] [PMID: 36474517]
[34]
Ocon, P.; Reguera, J.M.; Morata, P.; Juarez, C.; Alonso, A.; Colmenero, J.D. Phagocytic cell function in active brucellosis. Infect. Immun., 1994, 62(3), 910-914.
[http://dx.doi.org/10.1128/iai.62.3.910-914.1994] [PMID: 8112863]
[35]
Rizzo-Naudi, J.; Griscti-Soler, N.; Ganado, W. Human brucellosis: An evaluation of antibiotics in the treatment of brucellosis. Postgrad. Med. J., 1967, 43(502), 520-526.
[http://dx.doi.org/10.1136/pgmj.43.502.520] [PMID: 6074152]
[36]
Alizadeh, H.; Salouti, M.; Shapouri, R. Bactericidal effect of silver nanoparticles on intramacrophage Brucella abortus 544. Jundishapur J. Microbiol., 2014, 7(3), e9039.
[http://dx.doi.org/10.5812/jjm.9039] [PMID: 25147682]
[37]
Khan, A.U.; Shell, W.S.; Melzer, F.; Sayour, A.E.; Ramadan, E.S.; Elschner, M.C.; Moawad, A.A.; Roesler, U.; Neubauer, H.; El-Adawy, H. Identification, genotyping and antimicrobial susceptibility testing of Brucella spp. isolated from livestock in Egypt. Microorganisms, 2019, 7(12), 603.
[http://dx.doi.org/10.3390/microorganisms7120603] [PMID: 31766725]
[38]
Hashemi, S.H.; Gachkar, L.; Keramat, F.; Mamani, M.; Hajilooi, M.; Janbakhsh, A.; Majzoobi, M.M.; Mahjub, H. Comparison of doxycycline–streptomycin, doxycycline–rifampin, and ofloxacin–rifampin in the treatment of brucellosis: A randomized clinical trial. Int. J. Infect. Dis., 2012, 16(4), e247-e251.
[http://dx.doi.org/10.1016/j.ijid.2011.12.003] [PMID: 22296864]
[39]
Alavi, S.M.; Alavi, L. Treatment of brucellosis: A systematic review of studies in recent twenty years. Caspian J. Intern. Med., 2013, 4(2), 636-641.
[PMID: 24009951]
[40]
Johansen, T.B.; Scheffer, L.; Jensen, V.K.; Bohlin, J.; Feruglio, S.L. Whole-genome sequencing and antimicrobial resistance in Brucella melitensis from a Norwegian perspective. Sci. Rep., 2018, 8(1), 8538.
[http://dx.doi.org/10.1038/s41598-018-26906-3] [PMID: 29867163]
[41]
Majzoobi, M.M.; Hashmi, S.H.; Emami, K.; Soltanian, A.R. Combination of doxycycline, streptomycin and hydroxychloroquine for short-course treatment of brucellosis: A single-blind randomized clinical trial. Infection, 2022, 50(5), 1267-1271.
[http://dx.doi.org/10.1007/s15010-022-01806-x] [PMID: 35353333]
[42]
Peponis, V.; Kyttaris, V.C.; Chalkiadakis, S.E.; Bonovas, S.; Sitaras, N.M. Review: Ocular side effects of anti-rheumatic medications: What a rheumatologist should know. Lupus, 2010, 19(6), 675-682.
[http://dx.doi.org/10.1177/0961203309360539] [PMID: 20144965]
[43]
Shah, V.A.; Pandya, H.K.; Robinson, M.; Mandal, N. Hydroxychloroquine retinopathy: A review of imaging. Indian J. Ophthalmol., 2015, 63(7), 570-574.
[http://dx.doi.org/10.4103/0301-4738.167120] [PMID: 26458473]
[44]
del Pozo, J.S.G.; Solera, J. Treatment of human brucellosis-Review of evidence from clinical trials. In: Updates on Brucellosis; Baddour, M.M., Ed.; InTech, 2015. Available from:
[http://dx.doi.org/10.5772/59890.]
[45]
Hosseini, S.M.; Farmany, A.; Alikhani, M.Y.; Taheri, M.; Asl, S.S.; Alamian, S.; Arabestani, M.R. Co-Delivery of Doxycycline and hydroxychloroquine using CdTe-Labeled solid lipid nanoparticles for treatment of acute and chronic Brucellosis. Front Chem., 2022, 10, 890252.
[http://dx.doi.org/10.3389/fchem.2022.890252] [PMID: 35646816]
[46]
Zai, X.; Yin, Y.; Guo, F.; Yang, Q.; Li, R.; Li, Y.; Zhang, J.; Xu, J.; Chen, W. Screening of potential vaccine candidates against pathogenic Brucella spp. using compositive reverse vaccinology. Vet. Res., 2021, 52(1), 75.
[http://dx.doi.org/10.1186/s13567-021-00939-5] [PMID: 34078437]
[47]
Zhu, L.; Feng, Y.; Zhang, G.; Jiang, H.; Zhang, Z.; Wang, N.; Ding, J.; Suo, X. Brucella suis strain 2 vaccine is safe and protective against heterologous Brucella spp. infections. Vaccine, 2016, 34(3), 395-400.
[http://dx.doi.org/10.1016/j.vaccine.2015.09.116] [PMID: 26626213]
[48]
Chen, F.; He, Y. Caspase-2 mediated apoptotic and necrotic murine macrophage cell death induced by rough Brucella abortus. PLoS One, 2009, 4(8), e6830.
[http://dx.doi.org/10.1371/journal.pone.0006830] [PMID: 19714247]
[49]
Yang, X.; Skyberg, J.A.; Cao, L.; Clapp, B.; Thornburg, T.; Pascual, D.W. Progress in Brucella vaccine development. Front. Biol., 2013, 8(1), 60-77.
[http://dx.doi.org/10.1007/s11515-012-1196-0] [PMID: 23730309]
[50]
Wang, B. Drug design of zinc-enzyme inhibitors: Functional, structural, and disease applications; John Wiley & Sons, 2009.
[51]
Baglini, E.; Ravichandran, R.; Berrino, E.; Salerno, S.; Barresi, E.; Marini, A.M.; Viviano, M.; Castellano, S.; Da Settimo, F.; Supuran, C.T.; Cosconati, S.; Taliani, S. Tetrahydroquinazole-based secondary sulphonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IV, and IX, and computational studies. J. Enzyme Inhib. Med. Chem., 2021, 36(1), 1874-1883.
[http://dx.doi.org/10.1080/14756366.2021.1956913] [PMID: 34340614]
[52]
Winum, J.Y.; Köhler, S.; Supuran, C.T. Brucella carbonic anhydrases: New targets for designing anti-infective agents. Curr. Pharm. Des., 2010, 16(29), 3310-3316.
[http://dx.doi.org/10.2174/138161210793429850] [PMID: 20819063]
[53]
Joseph, P.; Turtaut, F.; Ouahrani-Bettache, S.; Montero, J.L.; Nishimori, I.; Minakuchi, T.; Vullo, D.; Scozzafava, A.; Köhler, S.; Winum, J.Y.; Supuran, C.T. Cloning, characterization, and inhibition studies of a beta-carbonic anhydrase from Brucella suis. J. Med. Chem., 2010, 53(5), 2277-2285.
[http://dx.doi.org/10.1021/jm901855h] [PMID: 20158185]
[54]
Lopez, M.; Köhler, S.; Winum, J.Y. Zinc metalloenzymes as new targets against the bacterial pathogen Brucella. J. Inorg. Biochem., 2012, 111, 138-145.
[http://dx.doi.org/10.1016/j.jinorgbio.2011.10.019] [PMID: 22196018]
[55]
Joseph, P.; Ouahrani-Bettache, S.; Montero, J.L.; Nishimori, I.; Minakuchi, T.; Vullo, D.; Scozzafava, A.; Winum, J.Y.; Köhler, S.; Supuran, C.T. A new β-carbonic anhydrase from Brucella suis, its cloning, characterization, and inhibition with sulfonamides and sulfamates, leading to impaired pathogen growth. Bioorg. Med. Chem., 2011, 19(3), 1172-1178.
[http://dx.doi.org/10.1016/j.bmc.2010.12.048] [PMID: 21251841]
[56]
Vullo, D.; Nishimori, I.; Scozzafava, A.; Köhler, S.; Winum, J.Y.; Supuran, C.T. Inhibition studies of a β-carbonic anhydrase from Brucella suis with a series of water soluble glycosyl sulfanilamides. Bioorg. Med. Chem. Lett., 2010, 20(7), 2178-2182.
[http://dx.doi.org/10.1016/j.bmcl.2010.02.042] [PMID: 20211561]
[57]
Riafrecha, L.E.; Vullo, D.; Supuran, C.T.; Colinas, P.A. C -glycosides incorporating the 6-methoxy-2-naphthyl moiety are selective inhibitors of fungal and bacterial carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2015, 30(5), 857-861.
[http://dx.doi.org/10.3109/14756366.2014.967233] [PMID: 25291009]
[58]
Ombouma, J.; Vullo, D.; Köhler, S.; Dumy, P.; Supuran, C.T.; Winum, J.Y. N-glycosyl-N-hydroxysulfamides as potent inhibitors of Brucella suis carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2015, 30(6), 1010-1012.
[http://dx.doi.org/10.3109/14756366.2014.986119] [PMID: 25792504]
[59]
Köhler, S.; Ouahrani-Bettache, S.; Winum, J.Y. Brucella suis carbonic anhydrases and their inhibitors: Towards alternative antibiotics? J. Enzyme Inhib. Med. Chem., 2017, 32(1), 683-687.
[http://dx.doi.org/10.1080/14756366.2017.1295451] [PMID: 28274160]
[60]
Maresca, A.; Scozzafava, A.; Köhler, S.; Winum, J.Y.; Supuran, C.T. Inhibition of beta-carbonic anhydrases from the bacterial pathogen Brucella suis with inorganic anions. J. Inorg. Biochem., 2012, 110, 36-39.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.02.009] [PMID: 22459172]
[61]
Ceruso, M.; Carta, F.; Osman, S.M.; Alothman, Z.; Monti, S.M.; Supuran, C.T. Inhibition studies of bacterial, fungal and protozoan β-class carbonic anhydrases with Schiff bases incorporating sulfonamide moieties. Bioorg. Med. Chem., 2015, 23(15), 4181-4187.
[http://dx.doi.org/10.1016/j.bmc.2015.06.050] [PMID: 26145821]
[62]
Vullo, D.; Del Prete, S.; Di Fonzo, P.; Carginale, V.; Donald, W.; Supuran, C.; Capasso, C. Comparison of the sulfonamide inhibition profiles of the β- and γ-carbonic anhydrases from the pathogenic bacterium Burkholderia pseudomallei. Molecules, 2017, 22(3), 421.
[http://dx.doi.org/10.3390/molecules22030421] [PMID: 28272358]
[63]
Köhler, S.; Foulongne, V.; Ouahrani-Bettache, S.; Bourg, G.; Teyssier, J.; Ramuz, M.; Liautard, J.P. The analysis of the intramacrophagic virulome of Brucella suis deciphers the environment encountered by the pathogen inside the macrophage host cell. Proc. Natl. Acad. Sci., 2002, 99(24), 15711-15716.
[http://dx.doi.org/10.1073/pnas.232454299] [PMID: 12438693]
[64]
Abdo, M.R.; Joseph, P.; Boigegrain, R.A.; Liautard, J.P.; Montero, J.L.; Köhler, S.; Winum, J.Y. Brucella suis histidinol dehydrogenase: Synthesis and inhibition studies of a series of substituted benzylic ketones derived from histidine. Bioorg. Med. Chem., 2007, 15(13), 4427-4433.
[http://dx.doi.org/10.1016/j.bmc.2007.04.027] [PMID: 17481905]
[65]
D’ambrosio, K.; Lopez, M.; Dathan, N.A.; Ouahrani-Bettache, S.; Köhler, S.; Ascione, G.; Monti, S.M.; Winum, J.Y.; De Simone, G. Structural basis for the rational design of new anti-Brucella agents: The crystal structure of the C366S mutant of l-histidinol dehydrogenase from Brucella suis. Biochimie, 2014, 97, 114-120.
[http://dx.doi.org/10.1016/j.biochi.2013.09.028] [PMID: 24140957]
[66]
Monti, S.M.; De Simone, G.; D’Ambrosio, K.S.; De Simone, G.; Ambrosio, K. L-Histidinol dehydrogenase as a new target for old diseases. Curr. Top. Med. Chem., 2016, 16(21), 2369-2378.
[http://dx.doi.org/10.2174/1568026616666160413140000] [PMID: 27072690]
[67]
Abdo, M.R.; Joseph, P.; Mortier, J.; Turtaut, F.; Montero, J.L.; Masereel, B.; Köhler, S.; Winum, J.Y. Anti-virulence strategy against Brucella suis: Synthesis, biological evaluation and molecular modeling of selective histidinol dehydrogenase inhibitors. Org. Biomol. Chem., 2011, 9(10), 3681-3690.
[http://dx.doi.org/10.1039/c1ob05149k] [PMID: 21461427]
[68]
Turtaut, F.; Lopez, M.; Ouahrani-Bettache, S.; Köhler, S.; Winum, J.Y. Oxo- and thiooxo-imidazo[1,5-c]pyrimidine molecule library: Beyond their interest in inhibition of Brucella suis histidinol dehydrogenase, a powerful protection tool in the synthesis of histidine analogues. Bioorg. Med. Chem. Lett., 2014, 24(21), 5008-5010.
[http://dx.doi.org/10.1016/j.bmcl.2014.09.020] [PMID: 25278235]
[69]
Turtaut, F.; Ouahrani-Bettache, S.; Montero, J.L.; Köhler, S.; Winum, J.Y. Synthesis and biological evaluation of a new class of anti-Brucella compounds targeting histidinol dehydrogenase: α-O-arylketones and α-S-arylketones derived from histidine. MedChemComm, 2011, 2(10), 995-1000.
[http://dx.doi.org/10.1039/c1md00146a]
[70]
Abdo, M.R.; Joseph, P.; Boigegrain, R.A.; Montero, J.L.; Köhler, S.; Winum, J.Y. Brucella suis histidinol dehydrogenase: Synthesis and inhibition studies of substituted N-L-histidinylphenylsulfonyl hydrazide. J. Enzyme Inhib. Med. Chem., 2008, 23(3), 357-361.
[http://dx.doi.org/10.1080/14756360701617107] [PMID: 18569340]
[71]
Green, E.R.; Mecsas, J. Bacterial secretion systems: An overview. Microbiol. Spectr., 2016, 4(1), 4.1.13..
[http://dx.doi.org/10.1128/microbiolspec.VMBF-0012-2015] [PMID: 26999395]
[72]
Baron, C. VirB8: a conserved type IV secretion system assembly factor and drug target. Biochem. Cell Biol., 2006, 84(6), 890-899.
[http://dx.doi.org/10.1139/o06-148] [PMID: 17215876]
[73]
O’Callaghan, D.; Cazevieille, C.; Allardet-Servent, A.; Boschiroli, M.L.; Bourg, G.; Foulongne, V.; Frutos, P.; Kulakov, Y.; Ramuz, M. A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis. Mol. Microbiol., 1999, 33(6), 1210-1220.
[http://dx.doi.org/10.1046/j.1365-2958.1999.01569.x] [PMID: 10510235]
[74]
Sieira, R.; Comerci, D.J.; Sánchez, D.O.; Ugalde, R.A. A homologue of an operon required for DNA transfer in Agrobacterium is required in Brucella abortus for virulence and intracellular multiplication. J. Bacteriol., 2000, 182(17), 4849-4855.
[http://dx.doi.org/10.1128/JB.182.17.4849-4855.2000] [PMID: 10940027]
[75]
Ke, Y.; Wang, Y.; Li, W.; Chen, Z. Type IV secretion system of Brucella spp. and its effectors. Front. Cell. Infect. Microbiol., 2015, 5, 72.
[http://dx.doi.org/10.3389/fcimb.2015.00072] [PMID: 26528442]
[76]
Xiong, X.; Li, B.; Zhou, Z.; Gu, G.; Li, M.; Liu, J.; Jiao, H. The VirB system plays a crucial role in Brucella intracellular infection. Int. J. Mol. Sci., 2021, 22(24), 13637.
[http://dx.doi.org/10.3390/ijms222413637] [PMID: 34948430]
[77]
Fronzes, R.; Schäfer, E.; Wang, L.; Saibil, H.R.; Orlova, E.V.; Waksman, G. Structure of a type IV secretion system core complex. Science, 2009, 323(5911), 266-268.
[http://dx.doi.org/10.1126/science.1166101] [PMID: 19131631]
[78]
Sun, Y.H.; Rolán, H.G.; den Hartigh, A.B.; Sondervan, D.; Tsolis, R.M. Brucella abortus virB12 is expressed during infection but is not an essential component of the type IV secretion system. Infect. Immun., 2005, 73(9), 6048-6054.
[http://dx.doi.org/10.1128/IAI.73.9.6048-6054.2005] [PMID: 16113325]
[79]
Atmakuri, K.; Cascales, E.; Christie, P.J. Energetic components VirD4, VirB11 and VirB4 mediate early DNA transfer reactions required for bacterial type IV secretion. Mol. Microbiol., 2004, 54(5), 1199-1211.
[http://dx.doi.org/10.1111/j.1365-2958.2004.04345.x] [PMID: 15554962]
[80]
Paschos, A.; Patey, G.; Sivanesan, D.; Gao, C.; Bayliss, R.; Waksman, G.; O’Callaghan, D.; Baron, C. Dimerization and interactions of Brucella suis VirB8 with VirB4 and VirB10 are required for its biological activity. Proc. Natl. Acad. Sci. USA, 2006, 103(19), 7252-7257.
[http://dx.doi.org/10.1073/pnas.0600862103] [PMID: 16648257]
[81]
Terradot, L.; Bayliss, R.; Oomen, C.; Leonard, G.A.; Baron, C.; Waksman, G. Structures of two core subunits of the bacterial type IV secretion system, VirB8 from Brucella suis and ComB10 from Helicobacter pylori. Proc. Natl. Acad. Sci. USA, 2005, 102(12), 4596-4601.
[http://dx.doi.org/10.1073/pnas.0408927102] [PMID: 15764702]
[82]
Paschos, A.; den Hartigh, A.; Smith, M.A.; Atluri, V.L.; Sivanesan, D.; Tsolis, R.M.; Baron, C. An in vivo high-throughput screening approach targeting the type IV secretion system component VirB8 identified inhibitors of Brucella abortus 2308 proliferation. Infect. Immun., 2011, 79(3), 1033-1043.
[http://dx.doi.org/10.1128/IAI.00993-10] [PMID: 21173315]
[83]
Smith, M.A.; Coinçon, M.; Paschos, A.; Jolicoeur, B.; Lavallée, P.; Sygusch, J.; Baron, C. Identification of the binding site of Brucella VirB8 interaction inhibitors. Chem. Biol., 2012, 19(8), 1041-1048.
[http://dx.doi.org/10.1016/j.chembiol.2012.07.007] [PMID: 22921071]
[84]
Sharifahmadian, M.; Arya, T.; Bessette, B.; Lecoq, L.; Ruediger, E.; Omichinski, J.G.; Baron, C. Monomer‐to‐dimer transition of Brucella suis type IV secretion system component VirB8 induces conformational changes. FEBS J., 2017, 284(8), 1218-1232.
[http://dx.doi.org/10.1111/febs.14049] [PMID: 28236662]
[85]
Woese, C.R.; Olsen, G.J.; Ibba, M.; Söll, D. Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process. Microbiol. Mol. Biol. Rev., 2000, 64(1), 202-236.
[http://dx.doi.org/10.1128/MMBR.64.1.202-236.2000] [PMID: 10704480]
[86]
Deniziak, M.A.; Barciszewski, J. Methionyl-tRNA synthetase. Acta Biochim. Pol., 2001, 48(2), 337-350.
[http://dx.doi.org/10.18388/abp.2001_3919] [PMID: 11732605]
[87]
Ojo, K.K.; Ranade, R.M.; Zhang, Z.; Dranow, D.M.; Myers, J.B.; Choi, R.; Nakazawa Hewitt, S.; Edwards, T.E.; Davies, D.R.; Lorimer, D.; Boyle, S.M.; Barrett, L.K.; Buckner, F.S.; Fan, E.; Van Voorhis, W.C. Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a potential drug target for Brucellosis. PLoS One, 2016, 11(8), e0160350.
[http://dx.doi.org/10.1371/journal.pone.0160350] [PMID: 27500735]
[88]
Shibata, S.; Gillespie, J.R.; Kelley, A.M.; Napuli, A.J.; Zhang, Z.; Kovzun, K.V.; Pefley, R.M.; Lam, J.; Zucker, F.H.; Van Voorhis, W.C.; Merritt, E.A.; Hol, W.G.J.; Verlinde, C.L.M.J.; Fan, E.; Buckner, F.S. Selective inhibitors of methionyl-tRNA synthetase have potent activity against Trypanosoma brucei infection in mice. Antimicrob. Agents Chemother., 2011, 55(5), 1982-1989.
[http://dx.doi.org/10.1128/AAC.01796-10] [PMID: 21282428]
[89]
Shibata, S.; Gillespie, J.R.; Ranade, R.M.; Koh, C.Y.; Kim, J.E.; Laydbak, J.U.; Zucker, F.H.; Hol, W.G.J.; Verlinde, C.L.M.J.; Buckner, F.S.; Fan, E. Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: Selectivity and in vivo characterization. J. Med. Chem., 2012, 55(14), 6342-6351.
[http://dx.doi.org/10.1021/jm300303e] [PMID: 22720744]
[90]
Regan, J.; Capolino, A.; Cirillo, P.F.; Gilmore, T.; Graham, A.G.; Hickey, E.; Kroe, R.R.; Madwed, J.; Moriak, M.; Nelson, R.; Pargellis, C.A.; Swinamer, A.; Torcellini, C.; Tsang, M.; Moss, N. Structure−activity relationships of the p38α MAP kinase inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph-thalen-1-yl]urea (BIRB 796). J. Med. Chem., 2003, 46(22), 4676-4686.
[http://dx.doi.org/10.1021/jm030121k] [PMID: 14561087]
[91]
Rowaiye, A.B.; Ogugua, A.J.; Ibeanu, G.; Bur, D.; Asala, M.T.; Ogbeide, O.B.; Abraham, E.O.; Usman, H.B. Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach. PLoS Negl. Trop. Dis., 2022, 16(3), e0009799.
[http://dx.doi.org/10.1371/journal.pntd.0009799] [PMID: 35312681]
[92]
Kumari, M.; chandra, S.; Tiwari, N.; Subbarao, N. High throughput virtual screening to identify novel natural product inhibitors for MethionyltRNA-Synthetase of Brucella melitensis. Bioinformation, 2017, 13(1), 8-16.
[http://dx.doi.org/10.6026/97320630013008] [PMID: 28479744]
[93]
Li, M.; Wen, F.; Zhao, S.; Wang, P.; Li, S.; Zhang, Y.; Zheng, N.; Wang, J. Exploring the molecular basis for binding of inhibitors by Threonyl-tRNA synthetase from Brucella abortus: A virtual screening study. Int. J. Mol. Sci., 2016, 17(7), 1078.
[http://dx.doi.org/10.3390/ijms17071078] [PMID: 27447614]
[94]
Powers, H.J. Riboflavin (vitamin B-2) and health. Am. J. Clin. Nutr., 2003, 77(6), 1352-1360.
[http://dx.doi.org/10.1093/ajcn/77.6.1352] [PMID: 12791609]
[95]
Walsh, C.T.; Wencewicz, T.A. Flavoenzymes: Versatile catalysts in biosynthetic pathways. Nat. Prod. Rep., 2013, 30(1), 175-200.
[http://dx.doi.org/10.1039/C2NP20069D] [PMID: 23051833]
[96]
Leys, D.; Scrutton, N.S. Sweating the assets of flavin cofactors: New insight of chemical versatility from knowledge of structure and mechanism. Curr. Opin. Struct. Biol., 2016, 41, 19-26.
[http://dx.doi.org/10.1016/j.sbi.2016.05.014] [PMID: 27266331]
[97]
Long, Q.; Ji, L.; Wang, H.; Xie, J. Riboflavin biosynthetic and regulatory factors as potential novel anti-infective drug targets. Chem. Biol. Drug Des., 2010, 75(4), 339-347.
[http://dx.doi.org/10.1111/j.1747-0285.2010.00946.x] [PMID: 20148904]
[98]
Moreno, A.; Taleb, V.; Sebastián, M.; Anoz-Carbonell, E.; Martínez-Júlvez, M.; Medina, M. Cofactors and pathogens: Flavin mononucleotide and flavin adenine dinucleotide (FAD) biosynthesis by the FAD synthase from Brucella ovis. IUBMB Life, 2022, 74(7), 655-671.
[http://dx.doi.org/10.1002/iub.2576] [PMID: 34813144]
[99]
Cushman, M.; Jin, G.; Illarionov, B.; Fischer, M.; Ladenstein, R.; Bacher, A.; Bacher, A. Design, synthesis, and biochemical evaluation of 1,5,6,7-tetrahydro-6,7-dioxo-9-D-ribitylaminolumazines bearing alkyl phosphate substituents as inhibitors of lumazine synthase and riboflavin synthase. J. Org. Chem., 2005, 70(20), 8162-8170.
[http://dx.doi.org/10.1021/jo051332v] [PMID: 16277343]
[100]
Zhang, Y.; Illarionov, B.; Morgunova, E.; Jin, G.; Bacher, A.; Fischer, M.; Ladenstein, R.; Cushman, M. A new series of N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimi-din-5-yl]oxalamic acid derivatives as inhibitors of lumazine synthase and riboflavin synthase: design, synthesis, biochemical evaluation, crystallography, and mechanistic implications. J. Org. Chem., 2008, 73(7), 2715-2724.
[http://dx.doi.org/10.1021/jo702631a] [PMID: 18331058]
[101]
Serer, M.I.; Bonomi, H.R.; Guimarães, B.G.; Rossi, R.C.; Goldbaum, F.A.; Klinke, S. Crystallographic and kinetic study of riboflavin synthase from Brucella abortus, a chemotherapeutic target with an enhanced intrinsic flexibility. Acta Crystallogr. D Biol. Crystallogr., 2014, 70(5), 1419-1434.
[http://dx.doi.org/10.1107/S1399004714005161] [PMID: 24816110]
[102]
Serer, M.I.; Carrica, M.C.; Trappe, J.; López Romero, S.; Bonomi, H.R.; Klinke, S.; Cerutti, M.L.; Goldbaum, F.A. A high‐throughput screening for inhibitors of riboflavin synthase identifies novel antimicrobial compounds to treat brucellosis. FEBS J., 2019, 286(13), 2522-2535.
[http://dx.doi.org/10.1111/febs.14829] [PMID: 30927485]
[103]
Kumar, R.; Bhakuni, V. A functionally active dimer of Mycobacterium tuberculosis malate synthase G. Eur. Biophys. J., 2010, 39(11), 1557-1562.
[http://dx.doi.org/10.1007/s00249-010-0598-7] [PMID: 20306314]
[104]
Adi, P.J.; Yellapu, N.K.; Matcha, B. Modeling, molecular docking, probing catalytic binding mode of acetyl-CoA malate synthase G in Brucella melitensis 16M. Biochem. Biophys. Rep., 2016, 8, 192-199.
[http://dx.doi.org/10.1016/j.bbrep.2016.08.020] [PMID: 28955956]
[105]
Muhammad, I.; Niaz, S.; Hussain, A.; Ahmad, S.; Rahman, N.; Khan, H.; Ali, A. Nayab, Gul E. Molecular docking and in vitro analysis of Fagonia cretica and Berberis lyceum extracts against Brucella melitensis. Curr. Computeraided Drug Des., 2021, 17(7), 946-956.
[http://dx.doi.org/10.2174/1573409916666200612145712] [PMID: 32532195]
[106]
Kamal, I.M.; Chakrabarti, S. MetaDOCK: A combinatorial molecular docking approach. ACS Omega, 2023, 8(6), 5850-5860.
[http://dx.doi.org/10.1021/acsomega.2c07619] [PMID: 36816658]
[107]
Pradeepkiran, J.A.; konidala, K.; Yellapu, N.; Bhaskar, M. Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M. Drug Des. Devel. Ther., 2015, 9, 1897-1912.
[http://dx.doi.org/10.2147/DDDT.S77020] [PMID: 25848225]
[108]
Kushwaha, S.K.; Shakya, M. Protein interaction network analysis—Approach for potential drug target identification in Mycobacterium tuberculosis. J. Theor. Biol., 2010, 262(2), 284-294.
[http://dx.doi.org/10.1016/j.jtbi.2009.09.029] [PMID: 19833135]
[109]
Gupta, M.; Prasad, Y.; Sharma, S.K.; Jain, C.K. Identification of Phosphoribosyl-AMP cyclohydrolase, as drug target and its inhibitors in Brucella melitensis bv. 1 16M using metabolic pathway analysis. J. Biomol. Struct. Dyn., 2017, 35(2), 287-299.
[http://dx.doi.org/10.1080/07391102.2015.1137229] [PMID: 26725317]
[110]
Mancini, D.T.; Matos, K.S.; da Cunha, E.F.F.; Assis, T.M.; Guimarães, A.P.; França, T.C.C.; Ramalho, T.C. Molecular modeling studies on nucleoside hydrolase from the biological warfare agent Brucella suis. J. Biomol. Struct. Dyn., 2012, 30(1), 125-136.
[http://dx.doi.org/10.1080/07391102.2012.674293] [PMID: 22571438]
[111]
Bie, P.; Yang, X.; Zhang, C.; Wu, Q. Identification of small-molecule inhibitors of Brucella diaminopimelate decarboxylase by using a high-throughput screening assay. Front. Microbiol., 2020, 10, 2936.
[http://dx.doi.org/10.3389/fmicb.2019.02936] [PMID: 32038511]
[112]
Scarff, J.M.; Waidyarachchi, S.L.; Meyer, C.J.; Lane, D.J.; Chai, W.; Lemmon, M.M.; Liu, J.; Butler, M.M.; Bowlin, T.L.; Lee, R.E.; Panchal, R.G. Aminomethyl spectinomycins: A novel antibacterial chemotype for biothreat pathogens. J. Antibiot., 2019, 72(9), 693-701.
[http://dx.doi.org/10.1038/s41429-019-0194-8] [PMID: 31164713]
[113]
Reuter, S.; Gupta, S.C.; Phromnoi, K.; Aggarwal, B.B. Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: A new use for an old drug. Br. J. Pharmacol., 2012, 165(7), 2127-2139.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01702.x] [PMID: 21955206]
[114]
Gross, A.; Terraza, A.; Marchant, J.; Bouaboula, M.; Ouahrani-Bettache, S.; Liautard, J.P.; Casellas, P.; Dornand, J. A beneficial aspect of a CB1 cannabinoid receptor antagonist: SR141716A is a potent inhibitor of macrophage infection by the intracellular pathogen Brucella suis. J. Leukoc. Biol., 2000, 67(3), 335-344.
[http://dx.doi.org/10.1002/jlb.67.3.335] [PMID: 10733093]
[115]
Boigegrain, R.A.; Liautard, J.P.; Köhler, S. Targeting of the virulence factor acetohydroxyacid synthase by sulfonylureas results in inhibition of intramacrophagic multiplication of Brucella suis. Antimicrob. Agents Chemother., 2005, 49(9), 3922-3925.
[http://dx.doi.org/10.1128/AAC.49.9.3922-3925.2005] [PMID: 16127072]
[116]
Kutlu, M.; Ergin, Ç.; Sen-Türk, N.; Sayin-Kutlu, S.; Zorbozan, O.; Akalın, S.; Şahin, B.; Çobankara, V.; Demirkan, N. Acute Brucella melitensis m16 infection model in mice treated with tumor necrosis factor-alpha inhibitors. J. Infect. Dev. Ctries., 2015, 9(2), 141-148.
[http://dx.doi.org/10.3855/jidc.5155] [PMID: 25699488]
[117]
Gagnaire, A.; Gorvel, L.; Papadopoulos, A.; Von Bargen, K.; Mège, J.L.; Gorvel, J.P. COX-2 inhibition reduces Brucella bacterial burden in draining lymph nodes. Front. Microbiol., 2016, 7, 1987.
[http://dx.doi.org/10.3389/fmicb.2016.01987] [PMID: 28018318]
[118]
Czyż, D.M.; Jain-Gupta, N.; Shuman, H.A.; Crosson, S. A dual-targeting approach to inhibit Brucella abortus replication in human cells. Sci. Rep., 2016, 6(1), 35835.
[http://dx.doi.org/10.1038/srep35835] [PMID: 27767061]
[119]
Reyes, A.W.B.; Hop, H.T.; Arayan, L.T.; Huy, T.X.N.; Min, W.; Lee, H.J.; Chang, H.H.; Kim, S. Nocodazole treatment interrupted Brucella abortus invasion in RAW 264.7 cells, and successfully attenuated splenic proliferation with enhanced inflammatory response in mice. Microb. Pathog., 2017, 103, 87-93.
[http://dx.doi.org/10.1016/j.micpath.2016.11.028] [PMID: 28017899]
[120]
Wang, Y.; Li, Y.; Li, H.; Song, H.; Zhai, N.; Lou, L.; Wang, F.; Zhang, K.; Bao, W.; Jin, X.; Su, L.; Tu, Z. Brucella dysregulates monocytes and inhibits macrophage polarization through LC3-Dependent autophagy. Front. Immunol., 2017, 8, 691.
[http://dx.doi.org/10.3389/fimmu.2017.00691] [PMID: 28659924]
[121]
Reyes, A.W.B.; Arayan, L.T.; Huy, T.X.N.; Vu, S.H.; Kang, C.K.; Min, W.; Lee, H.J.; Lee, J.H.; Kim, S. Chemokine receptor 4 (CXCR4) blockade enhances resistance to bacterial internalization in RAW264.7 cells and AMD3100, a CXCR4 antagonist, attenuates susceptibility to Brucella abortus 544 infection in a murine model. Vet. Microbiol., 2019, 237, 108402.
[http://dx.doi.org/10.1016/j.vetmic.2019.108402] [PMID: 31585647]
[122]
Nguyen, T.T.; Kim, H.; Huy, T.X.N.; Min, W.; Lee, H.; Reyes, A.W.B.; Lee, J.; Kim, S. Simvastatin inhibits Brucella abortus invasion into RAW 264.7 cells through suppression of the mevalonate pathway and promotes host immunity during infection in a mouse model. Int. J. Mol. Sci., 2022, 23(15), 8337.
[http://dx.doi.org/10.3390/ijms23158337] [PMID: 35955474]
[123]
Reyes, A.W.B.; Kim, H.; Huy, T.X.N.; Nguyen, T.T.; Min, W.; Lee, D.; Hur, J.; Lee, J.H.; Kim, S. The in vitro and in vivo effect of lipoxygenase pathway inhibitors nordihydroguaiaretic acid and its derivative tetra-O-methyl Nordihydroguaiaretic acid against Brucella abortus 544. J. Microbiol. Biotechnol., 2022, 32(9), 1126-1133.
[http://dx.doi.org/10.4014/jmb.2207.07026] [PMID: 36039381]
[124]
Reyes, A.W.B.; Vu, S.H.; Huy, T.X.N.; Min, W.; Lee, H.J.; Chang, H.H.; Lee, J.H.; Kim, S. Adenosine receptor Adora2b antagonism attenuates Brucella abortus 544 infection in professional phagocyte RAW 264.7 cells and BALB/c mice. Vet. Microbiol., 2020, 242, 108586.
[http://dx.doi.org/10.1016/j.vetmic.2020.108586] [PMID: 32122590]
[125]
Reyes, A.W.B.; Huy, T.X.N.; Vu, S.H.; Kang, C.K.; Min, W.; Lee, H.J.; Lee, J.H.; Kim, S. Formyl peptide receptor 2 (FPR2) antagonism is a potential target for the prevention of Brucella abortus 544 infection. Immunobiology, 2021, 226(3), 152073.
[http://dx.doi.org/10.1016/j.imbio.2021.152073] [PMID: 33657463]
[126]
Wang, L.L.; Chen, X.F.; Hu, P.; Lu, S.Y.; Fu, B.Q.; Li, Y.S.; Zhai, F.F.; Ju, D.D.; Zhang, S.J.; Shui, Y.M.; Chang, J.; Ma, X.L.; Su, B.; Zhou, Y.; Liu, Z.S.; Ren, H.L. Host Prdx6 contributing to the intracellular survival of Brucella suis S2 strain. BMC Vet. Res., 2019, 15(1), 304.
[http://dx.doi.org/10.1186/s12917-019-2049-8] [PMID: 31438945]

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      1.33msalphaeurekaselec_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 ('316374375','/article/134623',1,1740676800,1740676800)
      230μsalphaeurekaselec_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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) 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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) 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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) 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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) 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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) 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 >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316374375 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316374375) limit 1
      19.42msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316374375
      • 1: 316374375
      • 2: 316374375
      • 3: 316374375
      • 4: 316374375
      • 5: 316374375
      • 6: 316374375
      • 7: 316374375
      • 8: 316374375
      • 9: 316374375
      • 10: 316374375
      • 11: 316374375
      • 12: 316374375
      • 13: 316374375
      • 14: 316374375
      • 15: 316374375
      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=134623
      1.12msalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      1.32msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      2.16msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.75msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      5.65msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      4.81msalphaeurekaselec_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` = '134623'
      310μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 134623
      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` = '134623'
      23.29msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 134623
      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` = '134623' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      30.3msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 134623
      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 = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      93.54msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      55.85msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      44.17msalphaeurekaselec_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` = 134623 limit 1
      300μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 134623
      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 = 134623 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` = 221185 limit 1
      310μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 221185
      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
      330μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      520μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '134623' 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) )
      510μsalphaeurekaselec_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 = '13411' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      460μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '3436' 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) )
      430μsalphaeurekaselec_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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3436)
      9.01msalphaeurekaselec_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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13411)
      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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134623) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134623) 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 <= 316374375 and j.to_ip >=316374375 )) and ((j.from_date <= 1740676800 and j.to_date >= 1740676800 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134623)
      900μsalphaeurekaselec_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` < '4267' and is_uploaded = 1 and issue_id = 13411 order by cast(first_page as SIGNED) desc limit 1
      740μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 4267
      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` > '4285' and is_uploaded = 1 and issue_id = 13411 order by cast(first_page as SIGNED) asc limit 1
      660μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 4285
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      260μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      310μsalphaeurekaselec_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` = 134623 limit 1
      3.95msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 134623
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740676800 and `b`.`banner_to_date` >= 1740676800 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.61msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740676800
      • 4: 1740676800
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740676800 and `b`.`banner_to_date` >= 1740676800 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.71msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740676800
      • 4: 1740676800
      • 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='f0abde8375985d7bf76c3fea310c61a5'
      300μsalphaeurekaselec_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
        XPm1dtr3au4eR2qdRKzKBG3NAjtVtEhLYp1GlFK1
        uc_cart_id
        f0abde8375985d7bf76c3fea310c61a5
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/134623" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/134623
        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
        []
        
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