Generic placeholder image

Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides

Author(s): Kuldeep Singh*, Jeetendra Kumar Gupta, Shivendra Kumar and Urvashi Soni

Volume 25, Issue 7, 2024

Published on: 29 March, 2024

Page: [507 - 526] Pages: 20

DOI: 10.2174/0113892037275221240327042353

Price: $65

Abstract

Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.

Next »
Graphical Abstract

[1]
Lamptey, R.N.L.; Chaulagain, B.; Trivedi, R.; Gothwal, A.; Layek, B.; Singh, J. A review of the common neurodegenerative disorders: Current therapeutic approaches and the potential role of nanotherapeutics. Int. J. Mol. Sci., 2022, 23(3), 1851.
[http://dx.doi.org/10.3390/ijms23031851] [PMID: 35163773]
[2]
Palanisamy, C.P.; Pei, J.; Alugoju, P.; Anthikapalli, N.V.A.; Jayaraman, S.; Veeraraghavan, V.P.; Gopathy, S.; Roy, J.R.; Janaki, C.S.; Thalamati, D.; Mironescu, M.; Luo, Q.; Miao, Y.; Chai, Y.; Long, Q. New strategies of neurodegenerative disease treatment with extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs). Theranostics, 2023, 13(12), 4138-4165.
[http://dx.doi.org/10.7150/thno.83066] [PMID: 37554286]
[3]
Cobb, C.A.; Cole, M.P. Oxidative and nitrative stress in neurodegeneration. Neurobiol. Dis., 2015, 84, 4-21.
[http://dx.doi.org/10.1016/j.nbd.2015.04.020] [PMID: 26024962]
[4]
Wu, Y.; Angelova, A. Recent uses of lipid nanoparticles, cell-penetrating and bioactive peptides for the development of brain-targeted nanomedicines against neurodegenerative disorders. Nanomaterials, 2023, 13(23), 3004.
[http://dx.doi.org/10.3390/nano13233004] [PMID: 38063700]
[5]
Galland, F.; de Espindola, J.S.; Lopes, D.S.; Taccola, M.F.; Pacheco, M.T.B. Food-derived bioactive peptides: Mechanisms of action underlying inflammation and oxidative stress in the central nervous system. Food Chemist. Adv., 2022, 1, 100087.
[http://dx.doi.org/10.1016/j.focha.2022.100087]
[6]
Samtiya, M.; Samtiya, S.; Badgujar, P.C.; Puniya, A.K.; Dhewa, T.; Aluko, R.E. Health-promoting and therapeutic attributes of milk-derived bioactive peptides. Nutrients, 2022, 14(15), 3001.
[http://dx.doi.org/10.3390/nu14153001] [PMID: 35893855]
[7]
Li, Y.; Jin, T.; Liu, N.; Wang, J.; Qin, Z.; Yin, S.; Zhang, Y.; Fu, Z.; Wu, Y.; Wang, Y.; Liu, Y.; Yang, M.; Pang, A.; Sun, J.; Wang, Y.; Yang, X. A short peptide exerts neuroprotective effects on cerebral ischemia–reperfusion injury by reducing inflammation via the miR-6328/IKKβ/NF-κB axis. J. Neuroinflammation, 2023, 20(1), 53.
[http://dx.doi.org/10.1186/s12974-023-02739-4] [PMID: 36593485]
[8]
Urbán, N.; Guillemot, F. Neurogenesis in the embryonic and adult brain: Same regulators, different roles. Front. Cell. Neurosci., 2014, 8, 396.
[PMID: 25505873]
[9]
Huang, M.; Chen, S. DJ-1 in neurodegenerative diseases: Pathogenesis and clinical application. Prog. Neurobiol., 2021, 204, 102114.
[http://dx.doi.org/10.1016/j.pneurobio.2021.102114] [PMID: 34174373]
[10]
Fang, P.; Kazmi, S.A.; Jameson, K.G.; Hsiao, E.Y. The microbiome as a modifier of neurodegenerative disease risk. Cell Host Microbe, 2020, 28(2), 201-222.
[http://dx.doi.org/10.1016/j.chom.2020.06.008] [PMID: 32791113]
[11]
Li, P.; Feng, D.; Yang, D.; Li, X.; Sun, J.; Wang, G.; Tian, L.; Jiang, X.; Bai, W. Protective effects of anthocyanins on neurodegenerative diseases. Trends Food Sci. Technol., 2021, 117, 205-217.
[http://dx.doi.org/10.1016/j.tifs.2021.05.005]
[12]
Hao, J.J.; Hao, L.L. Review of clinical applications of scalp acupuncture for paralysis: An excerpt from chinese scalp acupuncture. Glob. Adv. Health Med., 2012, 1(1), 102-121.
[http://dx.doi.org/10.7453/gahmj.2012.1.1.017] [PMID: 24278807]
[13]
Gulisano, W.; Maugeri, D.; Baltrons, M.A.; Fà, M.; Amato, A.; Palmeri, A.; D’Adamio, L.; Grassi, C.; Devanand, D.P.; Honig, L.S.; Puzzo, D.; Arancio, O. Role of amyloid-β and tau proteins in alzheimer’s disease: Confuting the amyloid cascade. J. Alzheimers Dis., 2018, 64(S1), S611-S631.
[http://dx.doi.org/10.3233/JAD-179935] [PMID: 29865055]
[14]
Dhikav, V.; Anand, K.S. Hippocampus in health and disease: An overview. Ann. Indian Acad. Neurol., 2012, 15(4), 239-246.
[http://dx.doi.org/10.4103/0972-2327.104323] [PMID: 23349586]
[15]
Jahn, H. Memory loss in Alzheimer’s disease. Dialogues Clin. Neurosci., 2013, 15(4), 445-454.
[http://dx.doi.org/10.31887/DCNS.2013.15.4/hjahn] [PMID: 24459411]
[16]
DeMaagd, G.; Philip, A. Parkinson’s disease and its management: Part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. Pharm. Therapeut., 2015, 40(8), 504-532.
[PMID: 26236139]
[17]
Bartels, A.L.; Leenders, K.L. Parkinson’s disease: The syndrome, the pathogenesis and pathophysiology. Cortex, 2009, 45(8), 915-921.
[http://dx.doi.org/10.1016/j.cortex.2008.11.010] [PMID: 19095226]
[18]
Giguère, N.; Nanni, B.S.; Trudeau, L.E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol., 2018, 9, 455.
[http://dx.doi.org/10.3389/fneur.2018.00455] [PMID: 29971039]
[19]
Ashraf, G.; Greig, N.; Khan, T.; Hassan, I.; Tabrez, S.; Shakil, S.; Sheikh, I.; Zaidi, S.; Akram, M.; Jabir, N.; Firoz, C.; Naeem, A.; Alhazza, I.; Damanhouri, G.; Kamal, M. Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol. Disord. Drug Targets, 2014, 13(7), 1280-1293.
[http://dx.doi.org/10.2174/1871527313666140917095514] [PMID: 25230234]
[20]
Kins, S.; Lauther, N.; Szodorai, A.; Beyreuther, K. Subcellular trafficking of the amyloid precursor protein gene family and its pathogenic role in Alzheimer’s disease. Neurodegener. Dis., 2006, 3(4-5), 218-226.
[http://dx.doi.org/10.1159/000095259] [PMID: 17047360]
[21]
Sheikh, S.; Safia; Haque, E.; Mir, S.S. Neurodegenerative diseases: Multifactorial conformational diseases and their therapeutic interventions. J. Neurodegener. Dis., 2013, 2013, 1-8.
[http://dx.doi.org/10.1155/2013/563481]
[22]
Parsons, M.P.; Raymond, L.A. Huntington Disease, 2nd ed; StatPearls Publishing: Treasure Island (FL), 2023, pp. 275-292.
[23]
Paulsen, J.S. Cognitive impairment in Huntington disease: Diagnosis and treatment. Curr. Neurol. Neurosci. Rep., 2011, 11(5), 474-483.
[http://dx.doi.org/10.1007/s11910-011-0215-x] [PMID: 21861097]
[24]
Labbadia, J.; Morimoto, R.I. Huntington’s disease: Underlying molecular mechanisms and emerging concepts. Trends Biochem. Sci., 2013, 38(8), 378-385.
[http://dx.doi.org/10.1016/j.tibs.2013.05.003] [PMID: 23768628]
[25]
Kim, A.; Lalonde, K.; Truesdell, A.; Welter, G.P.; Brocardo, P.S.; Rosenstock, T.R.; Mohapel, G.J. New avenues for the treatment of huntington’s disease. Int. J. Mol. Sci., 2021, 22(16), 8363.
[http://dx.doi.org/10.3390/ijms22168363] [PMID: 34445070]
[26]
Mühlbӓck, A.; van Walsem, M.; Nance, M.; Arnesen, A.; Page, K.; Fisher, A.; van Kampen, M.; Nuzzi, A.; Limpert, R.; Fossmo, H.L.; Cruickshank, T.; Veenhuizen, R. What we don’t need to prove but need to do in multidisciplinary treatment and care in Huntington’s disease: A position paper. Orphanet J. Rare Dis., 2023, 18(1), 19.
[http://dx.doi.org/10.1186/s13023-023-02622-8] [PMID: 36717864]
[27]
Zarei, S.; Carr, K.; Reiley, L.; Diaz, K.; Guerra, O.; Altamirano, P.; Pagani, W.; Lodin, D.; Orozco, G.; Chinea, A. A comprehensive review of amyotrophic lateral sclerosis. Surg. Neurol. Int., 2015, 6(1), 171.
[http://dx.doi.org/10.4103/2152-7806.169561] [PMID: 26629397]
[28]
Suzuki, N.; Nishiyama, A.; Warita, H.; Aoki, M. Genetics of amyotrophic lateral sclerosis: Seeking therapeutic targets in the era of gene therapy. J. Hum. Genet., 2023, 68(3), 131-152.
[http://dx.doi.org/10.1038/s10038-022-01055-8] [PMID: 35691950]
[29]
Masrori, P.; Van Damme, P. Amyotrophic lateral sclerosis: A clinical review. Eur. J. Neurol., 2020, 27(10), 1918-1929.
[http://dx.doi.org/10.1111/ene.14393] [PMID: 32526057]
[30]
Blokhuis, A.M.; Groen, E.J.N.; Koppers, M.; van den Berg, L.H.; Pasterkamp, R.J. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol., 2013, 125(6), 777-794.
[http://dx.doi.org/10.1007/s00401-013-1125-6] [PMID: 23673820]
[31]
Mortada, I.; Farah, R.; Nabha, S.; Ojcius, D.M.; Fares, Y.; Almawi, W.Y.; Sadier, N.S. Immunotherapies for neurodegenerative diseases. Front. Neurol., 2021, 12, 654739.
[http://dx.doi.org/10.3389/fneur.2021.654739] [PMID: 34163421]
[32]
Yiannopoulou, K.G.; Papageorgiou, S.G. Current and future treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord., 2013, 6(1), 19-33.
[http://dx.doi.org/10.1177/1756285612461679] [PMID: 23277790]
[33]
Ali, R.; Gupta, G.D.; Chawla, P.A. Aducanumab: A new hope in Alzheimer’s disease. Health Sci. Rep., 2022, 4, 100039.
[http://dx.doi.org/10.1016/j.hsr.2022.100039]
[34]
Behl, T.; Kaur, I.; Sehgal, A.; Singh, S.; Sharma, N.; Makeen, H.A.; Albratty, M.; Alhazmi, H.A.; Felemban, S.G.; Alsubayiel, A.M.; Bhatia, S.; Bungau, S. “Aducanumab” making a comeback in Alzheimer’s disease: An old wine in a new bottle. Biomed. Pharmacother., 2022, 148, 112746.
[http://dx.doi.org/10.1016/j.biopha.2022.112746] [PMID: 35231697]
[35]
Imbimbo, B.P.; Ippati, S.; Watling, M.; Imbimbo, C. Role of monomeric amyloid-β in cognitive performance in Alzheimer’s disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacol. Res., 2023, 187, 106631.
[http://dx.doi.org/10.1016/j.phrs.2022.106631] [PMID: 36586644]
[36]
Ji, C.; Sigurdsson, E.M. Current status of clinical trials on tau immunotherapies. Drugs, 2021, 81(10), 1135-1152.
[http://dx.doi.org/10.1007/s40265-021-01546-6] [PMID: 34101156]
[37]
Grossberg, G.T. Cholinesterase inhibitors for the treatment of Alzheimer’s disease: Getting on and staying on. Curr. Ther. Res. Clin. Exp., 2003, 64(4), 216-235.
[http://dx.doi.org/10.1016/S0011-393X(03)00059-6] [PMID: 24944370]
[38]
Marucci, G.; Buccioni, M.; Ben, D.D.; Lambertucci, C.; Volpini, R.; Amenta, F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology, 2021, 190, 108352.
[http://dx.doi.org/10.1016/j.neuropharm.2020.108352] [PMID: 33035532]
[39]
Kandiah, N.; Pai, M.C.; Senanarong, V.; Looi, I.; Ampil, E.; Park, K.W.; Karanam, A.K.; Christopher, S. Rivastigmine: The advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson’s disease dementia. Clin. Interv. Aging, 2017, 12, 697-707.
[http://dx.doi.org/10.2147/CIA.S129145] [PMID: 28458525]
[40]
Esang, M.; Gupta, M. Aducanumab as a novel treatment for alzheimer’s disease: A decade of hope, controversies, and the future. Cureus, 2021, 13(8), e17591.
[http://dx.doi.org/10.7759/cureus.17591] [PMID: 34646644]
[41]
Shi, M.; Chu, F.; Zhu, F.; Zhu, J. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of alzheimer’s disease: A focus on aducanumab and lecanemab. Front. Aging Neurosci., 2022, 14, 870517.
[http://dx.doi.org/10.3389/fnagi.2022.870517] [PMID: 35493943]
[42]
Wang, R.; Reddy, P.H. Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis., 2017, 57(4), 1041-1048.
[http://dx.doi.org/10.3233/JAD-160763] [PMID: 27662322]
[43]
Tariot, P.N.; Farlow, M.R.; Grossberg, G.T.; Graham, S.M.; McDonald, S.; Gergel, I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA, 2004, 291(3), 317-324.
[http://dx.doi.org/10.1001/jama.291.3.317] [PMID: 14734594]
[44]
Paul, A.; Yadav, K.S. Parkinson’s disease: Current drug therapy and unraveling the prospects of nanoparticles. J. Drug Deliv. Sci. Technol., 2020, 58, 101790.
[http://dx.doi.org/10.1016/j.jddst.2020.101790]
[45]
Ovallath, S.; Sulthana, B. Levodopa: History and therapeutic applications. Ann. Indian Acad. Neurol., 2017, 20(3), 185-189.
[http://dx.doi.org/10.4103/aian.AIAN_241_17] [PMID: 28904446]
[46]
Kelley, BJ; Duker, AP; Chiu, P Dopamine agonists and pathologic behaviors. Parkinsons Dis., 2012, 2012, 603631.
[http://dx.doi.org/10.1155/2012/603631]
[47]
Emmady, P.D.; Schoo, C.; Tadi, P. Major neurocognitive disorder (Dementia). In: StatPearls; StatPearls Publishing: Treasure Island (FL), 2022.
[48]
Alghamdi, B.S. The neuroprotective role of melatonin in neurological disorders. J. Neurosci. Res., 2018, 96(7), 1136-1149.
[http://dx.doi.org/10.1002/jnr.24220] [PMID: 29498103]
[49]
Seino, Y.; Fukushima, M.; Yabe, D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J. Diabetes Investig., 2010, 1(1-2), 8-23.
[http://dx.doi.org/10.1111/j.2040-1124.2010.00022.x] [PMID: 24843404]
[50]
Aksoy, D.; Solmaz, V.; Çavuşoğlu, T.; Meral, A.; Ateş, U.; Erbaş, O. Neuroprotective effects of eexenatide in a rotenone-induced rat model of parkinson’s disease. Am. J. Med. Sci., 2017, 354(3), 319-324.
[http://dx.doi.org/10.1016/j.amjms.2017.05.002] [PMID: 28918840]
[51]
Grotemeyer, A.; McFleder, R.L.; Wu, J.; Wischhusen, J.; Ip, C.W. Neuroinflammation in parkinson’s disease – putative pathomechanisms and targets for disease-modification. Front. Immunol., 2022, 13, 878771.
[http://dx.doi.org/10.3389/fimmu.2022.878771] [PMID: 35663989]
[52]
Kang, M.Y.; Oh, T.J.; Cho, Y.M. Glucagon-like peptide-1 increases mitochondrial biogenesis and function in INS-1 rat insulinoma cells. Endocrinol. Metab., 2015, 30(2), 216-220.
[http://dx.doi.org/10.3803/EnM.2015.30.2.216] [PMID: 26194081]
[53]
Salcedo, I.; Tweedie, D.; Li, Y.; Greig, N.H. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: An emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharmacol., 2012, 166(5), 1586-1599.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01971.x] [PMID: 22519295]
[54]
Glotfelty, E.J.; Olson, L.; Karlsson, T.E.; Li, Y.; Greig, N.H. Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson’s disease. Expert Opin. Investig. Drugs, 2020, 29(6), 595-602.
[http://dx.doi.org/10.1080/13543784.2020.1764534] [PMID: 32412796]
[55]
Karpiesiuk, A.; Palus, K. Pituitary adenylate cyclase-activating polypeptide (PACAP) in physiological and pathological processes within the gastrointestinal tract: A review. Int. J. Mol. Sci., 2021, 22(16), 8682.
[http://dx.doi.org/10.3390/ijms22168682] [PMID: 34445388]
[56]
Hirabayashi, T.; Nakamachi, T.; Shioda, S. Discovery of PACAP and its receptors in the brain. J. Headache Pain, 2018, 19(1), 28.
[http://dx.doi.org/10.1186/s10194-018-0855-1] [PMID: 29619773]
[57]
Dong, D.; Xie, J.; Wang, J. Neuroprotective effects of brain-gut peptides: A potential therapy for parkinson’s disease. Neurosci. Bull., 2019, 35(6), 1085-1096.
[http://dx.doi.org/10.1007/s12264-019-00407-3] [PMID: 31286411]
[58]
Johnson, M.B.; Young, A.D.; Marriott, I. The therapeutic potential of targeting substance P/NK-1R interactions in inflammatory CNS disorders. Front. Cell. Neurosci., 2016, 10, 296.
[PMID: 28101005]
[59]
Cherait, A.; Banks, W.A.; Vaudry, D. The potential of the nose-to-brain delivery of PACAP for the treatment of neuronal disease. Pharmaceutics, 2023, 15(8), 2032.
[http://dx.doi.org/10.3390/pharmaceutics15082032] [PMID: 37631246]
[60]
Ramesh, N.; Mohan, H.; Unniappan, S. Nucleobindin-1 encodes a nesfatin-1-like peptide that stimulates insulin secretion. Gen. Comp. Endocrinol., 2015, 216, 182-189.
[http://dx.doi.org/10.1016/j.ygcen.2015.04.011] [PMID: 25907657]
[61]
Ayada, C.; Toru, Ü.; Korkut, Y. Nesfatin-1 and its effects on different systems. Hippokratia, 2015, 19(1), 4-10.
[PMID: 26435639]
[62]
Esposito, E; Matteo, D.V; Benigno, A; Pierucci, M; Crescimanno, G; Giovanni, D.G Non-steroidal anti-inflammatory drugs in Parkinson’s disease. Exp. Neurol., 2007, 205(2), 295-312.
[http://dx.doi.org/10.1016/j.expneurol.2007.02.008]
[63]
Shen, X.L.; Song, N.; Du, X.X.; Li, Y.; Xie, J.X.; Jiang, H. Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf–ERK1/2-dependent anti-apoptotic pathway. Sci. Rep., 2017, 7(1), 40961.
[http://dx.doi.org/10.1038/srep40961]
[64]
Kwon, H.S.; Koh, S.H. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Transl. Neurodegener., 2020, 9(1), 42.
[http://dx.doi.org/10.1186/s40035-020-00221-2] [PMID: 33239064]
[65]
Wang, Q.; Liu, Y.; Zhou, J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl. Neurodegener., 2015, 4(1), 19.
[http://dx.doi.org/10.1186/s40035-015-0042-0] [PMID: 26464797]
[66]
Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999, 402(6762), 656-660.
[http://dx.doi.org/10.1038/45230] [PMID: 10604470]
[67]
Akalu, Y; Molla, MD; Dessie, G; Ayelign, B Physiological effect of ghrelin on body systems. Int. J. Endocrinol., 2020, 2020, 1385138.
[http://dx.doi.org/10.1155/2020/1385138]
[68]
Russo, C.; Valle, M.S.; Russo, A.; Malaguarnera, L. The interplay between ghrelin and microglia in neuroinflammation: Implications for obesity and neurodegenerative diseases. Int. J. Mol. Sci., 2022, 23(21), 13432.
[http://dx.doi.org/10.3390/ijms232113432] [PMID: 36362220]
[69]
Sanchez, J.M.; Licitra, F.; Underwood, B.R.; Rubinsztein, D.C. Huntington’s Disease: Mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb. Perspect. Med., 2017, 7(7), a024240.
[http://dx.doi.org/10.1101/cshperspect.a024240] [PMID: 27940602]
[70]
De Tommaso, M.; Serpino, C.; Sciruicchio, V. Management of Huntington’s disease: Role of tetrabenazine. Ther. Clin. Risk Manag., 2011, 7, 123-129.
[http://dx.doi.org/10.2147/TCRM.S17152] [PMID: 21479143]
[71]
Ding, J; Gadit, AM Psychosis with Huntington's disease: Role of antipsychotic medications. BMJ Case Rep., 2014, 2014, bcr2013202625.
[72]
Dong, X.; Wang, Y.; Qin, Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol. Sin., 2009, 30(4), 379-387.
[http://dx.doi.org/10.1038/aps.2009.24] [PMID: 19343058]
[73]
Bathina, S.; Das, U.N. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci., 2015, 6(6), 1164-1178.
[http://dx.doi.org/10.5114/aoms.2015.56342] [PMID: 26788077]
[74]
Alkanli, S.S.; Alkanli, N.; Ay, A.; Albeniz, I. CRISPR/Cas9 mediated therapeutic approach in Huntington’s Disease. Mol. Neurobiol., 2023, 60(3), 1486-1498.
[http://dx.doi.org/10.1007/s12035-022-03150-5] [PMID: 36482283]
[75]
Yang, S.; Chang, R.; Yang, H.; Zhao, T.; Hong, Y.; Kong, H.E.; Sun, X.; Qin, Z.; Jin, P.; Li, S.; Li, X.J. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J. Clin. Invest., 2017, 127(7), 2719-2724.
[http://dx.doi.org/10.1172/JCI92087] [PMID: 28628038]
[76]
Berlet, R.; Anthony, S.; Brooks, B.; Wang, Z.J.; Sadanandan, N.; Shear, A.; Cozene, B.; Portillo, G.B.; Parsons, B.; Salazar, F.E.; Toledo, L.A.R.; Monroy, G.R.; Portillo, G.J.V.; Borlongan, C.V. Combination of stem cells and rehabilitation therapies for ischemic stroke. Biomolecules, 2021, 11(9), 1316.
[http://dx.doi.org/10.3390/biom11091316] [PMID: 34572529]
[77]
Vazin, T.; Freed, W.J. Human embryonic stem cells: Derivation, culture, and differentiation: A review. Restor. Neurol. Neurosci., 2010, 28(4), 589-603.
[http://dx.doi.org/10.3233/RNN-2010-0543] [PMID: 20714081]
[78]
Rajput, A.; Varshney, A.; Bajaj, R.; Pokharkar, V. Exosomes as new generation vehicles for drug delivery: Biomedical applications and future perspectives. Molecules, 2022, 27(21), 7289.
[http://dx.doi.org/10.3390/molecules27217289] [PMID: 36364116]
[79]
Saba, J.; Couselo, F.L.; Bruno, J.; Carniglia, L.; Durand, D.; Lasaga, M.; Caruso, C. Neuroinflammation in Huntington’s Disease: A starring role for astrocyte and microglia. Curr. Neuropharmacol., 2022, 20(6), 1116-1143.
[http://dx.doi.org/10.2174/1570159X19666211201094608] [PMID: 34852742]
[80]
Nowicka, N.; Juranek, J.; Juranek, J.K.; Wojtkiewicz, J. Risk factors and emerging therapies in amyotrophic lateral sclerosis. Int. J. Mol. Sci., 2019, 20(11), 2616.
[http://dx.doi.org/10.3390/ijms20112616] [PMID: 31141951]
[81]
Okada, M.; Yamashita, S.; Ueyama, H.; Ishizaki, M.; Maeda, Y.; Ando, Y. Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis. eNeurologicalSci, 2018, 11, 11-14.
[http://dx.doi.org/10.1016/j.ensci.2018.05.001] [PMID: 29928711]
[82]
Mouhammad, Z.A.; Vohra, R.; Horwitz, A.; Thein, A.S.; Rovelt, J.; Cvenkel, B.; Williams, P.A.; Blanco, A.A.; Kolko, M. Glucagon-like peptide 1 receptor agonists – potential game changers in the treatment of glaucoma? Front. Neurosci., 2022, 16, 824054.
[http://dx.doi.org/10.3389/fnins.2022.824054] [PMID: 35264926]
[83]
Wang, S.; Sun-Waterhouse, D.; Neil Waterhouse, G.I.; Zheng, L.; Su, G.; Zhao, M. Effects of food-derived bioactive peptides on cognitive deficits and memory decline in neurodegenerative diseases: A review. Trends Food Sci. Technol., 2021, 116, 712-732.
[http://dx.doi.org/10.1016/j.tifs.2021.04.056]
[84]
Yeo, X.Y.; Cunliffe, G.; Ho, R.C.; Lee, S.S.; Jung, S. Potentials of neuropeptides as therapeutic agents for Neurological Diseases. Biomedicines, 2022, 10(2), 343.
[http://dx.doi.org/10.3390/biomedicines10020343] [PMID: 35203552]
[85]
Sakthiswary, R.; Raymond, A.A. Stem cell therapy in neurodegenerative diseases: From principles to practice. Neural Regen. Res., 2012, 7(23), 1822-1831.
[PMID: 25624807]
[86]
Lee, A.C.L.; Harris, J.L.; Khanna, K.K.; Hong, J.H. A comprehensive review on current advances in peptide drug development and design. Int. J. Mol. Sci., 2019, 20(10), 2383.
[http://dx.doi.org/10.3390/ijms20102383] [PMID: 31091705]
[87]
Strafella, C.; Caputo, V.; Galota, M.R.; Zampatti, S.; Marella, G.; Mauriello, S.; Cascella, R.; Giardina, E. Application of precision medicine in Neurodegenerative Diseases. Front. Neurol., 2018, 9, 701.
[http://dx.doi.org/10.3389/fneur.2018.00701] [PMID: 30190701]
[88]
Malviya, R.; Singh, A.K.; Verma, S. Personalized medicine: Advanced treatment strategies to revolutionize healthcare. Curr. Drug Res. Rev., 2023, 15(2), 101-104.
[http://dx.doi.org/10.2174/2589977515666221104152641] [PMID: 36336809]
[89]
Mahdieh, N.; Rabbani, B. An overview of mutation detection methods in genetic disorders. Iran. J. Pediatr., 2013, 23(4), 375-388.
[PMID: 24427490]
[90]
Mathur, S.; Sutton, J. Personalized medicine could transform healthcare. Biomed. Rep., 2017, 7(1), 3-5.
[http://dx.doi.org/10.3892/br.2017.922] [PMID: 28685051]
[91]
Raghunathan, R.; Turajane, K.; Wong, L.C. Biomarkers in neurodegenerative diseases: Proteomics spotlight on ALS and Parkinson’s Disease. Int. J. Mol. Sci., 2022, 23(16), 9299.
[http://dx.doi.org/10.3390/ijms23169299] [PMID: 36012563]
[92]
Li, L.; Wu, J.; Lyon, C.J.; Jiang, L.; Hu, T.Y. Clinical peptidomics: Advances in instrumentation, analyses, and applications. BME Front., 2023, 4, 0019.
[93]
Strianese, O.; Rizzo, F.; Ciccarelli, M.; Galasso, G.; D’Agostino, Y.; Salvati, A.; Del Giudice, C.; Tesorio, P.; Rusciano, M.R. Precision and personalized medicine: how genomic approach improves the management of cardiovascular and neurodegenerative disease. Genes, 2020, 11(7), 747.
[http://dx.doi.org/10.3390/genes11070747] [PMID: 32640513]
[94]
Alowais, S.A.; Alghamdi, S.S.; Alsuhebany, N.; Alqahtani, T.; Alshaya, A.I.; Almohareb, S.N.; Aldairem, A.; Alrashed, M.; Saleh, B.K.; Badreldin, H.A.; Yami, A.M.S.; Harbi, A.S.; Albekairy, A.M. Revolutionizing healthcare: The role of artificial intelligence in clinical practice. BMC Med. Educ., 2023, 23(1), 689.
[http://dx.doi.org/10.1186/s12909-023-04698-z] [PMID: 37740191]
[95]
Goetz, L.H.; Schork, N.J. Personalized medicine: Motivation, challenges, and progress. Fertil. Steril., 2018, 109(6), 952-963.
[http://dx.doi.org/10.1016/j.fertnstert.2018.05.006] [PMID: 29935653]
[96]
Stoddard, H.B.M.; Smith, J.J. Precision medicine clinical trials: Defining new treatment strategies. Semin. Oncol. Nurs., 2014, 30(2), 109-116.
[http://dx.doi.org/10.1016/j.soncn.2014.03.004] [PMID: 24794084]
[97]
Chen, W.; Hu, Y.; Ju, D. Gene therapy for neurodegenerative disorders: Advances, insights and prospects. Acta Pharm. Sin. B, 2020, 10(8), 1347-1359.
[http://dx.doi.org/10.1016/j.apsb.2020.01.015] [PMID: 32963936]
[98]
Gupta, J.K.; Singh, K. Pharmacological potential of bioactive peptides for the treatment of diseases associated with alzheimer’s and brain disorders. Curr. Mol. Med., 2023, 2023, 23.
[PMID: 37691200]
[99]
Akbarian, M.; Khani, A.; Eghbalpour, S.; Uversky, V.N. Bioactive peptides: Synthesis, sources, applications, and proposed mechanisms of action. Int. J. Mol. Sci., 2022, 23(3), 1445.
[http://dx.doi.org/10.3390/ijms23031445] [PMID: 35163367]
[100]
Zaky, A.A.; Gandara, S.J.; Eun, J.B.; Shim, J.H.; Aty, A.E.A.M. Bioactivities, applications, safety, and health benefits of bioactive peptides from food and by-products: A review. Front. Nutr., 2021, 8, 815640.
[PMID: 35127796]
[101]
Pilozzi, A.; Carro, C.; Huang, X. Roles of β-endorphin in stress, behavior, neuroinflammation, and brain energy metabolism. Int. J. Mol. Sci., 2020, 22(1), 338.
[http://dx.doi.org/10.3390/ijms22010338] [PMID: 33396962]
[102]
Klein, J.A.; Ackerman, S.L. Oxidative stress, cell cycle, and neurodegeneration. J. Clin. Invest., 2003, 111(6), 785-793.
[http://dx.doi.org/10.1172/JCI200318182] [PMID: 12639981]
[103]
Lee, S.Y.; Hur, S.J. Mechanisms of neuroprotective effects of peptides derived from natural materials and their production and assessment. Compr. Rev. Food Sci. Food Saf., 2019, 18(4), 923-935.
[http://dx.doi.org/10.1111/1541-4337.12451] [PMID: 33336993]
[104]
Ögren, S.O.; Kuteeva, E.; Tottie, E.E.; Hökfelt, T. Neuropeptides in learning and memory processes with focus on galanin. Eur. J. Pharmacol., 2010, 626(1), 9-17.
[http://dx.doi.org/10.1016/j.ejphar.2009.09.070] [PMID: 19837050]
[105]
Hayes, M.; Tiwari, B. Bioactive carbohydrates and peptides in foods: an overview of sources, downstream processing steps and associated bioactivities. Int. J. Mol. Sci., 2015, 16(9), 22485-22508.
[http://dx.doi.org/10.3390/ijms160922485] [PMID: 26393573]
[106]
Sim, A.Y.; Barua, S.; Kim, J.Y.; Lee, Y.; Lee, J.E. Role of DPP-4 and SGLT2 inhibitors connected to alzheimer disease in type 2 diabetes mellitus. Front. Neurosci., 2021, 15, 708547.
[http://dx.doi.org/10.3389/fnins.2021.708547] [PMID: 34489627]
[107]
Chen, G.; Xu, T.; Yan, Y.; Zhou, Y.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin., 2017, 38(9), 1205-1235.
[http://dx.doi.org/10.1038/aps.2017.28] [PMID: 28713158]
[108]
Stefanis, L. α-Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med., 2012, 2(2), a009399.
[http://dx.doi.org/10.1101/cshperspect.a009399] [PMID: 22355802]
[109]
Ibrahim, A.M.; Chauhan, L.; Bhardwaj, A.; Sharma, A.; Fayaz, F.; Kumar, B.; Alhashmi, M.; AlHajri, N.; Alam, M.S.; Pottoo, F.H. Brain-derived neurotropic factor in neurodegenerative disorders. Biomedicines, 2022, 10(5), 1143.
[http://dx.doi.org/10.3390/biomedicines10051143] [PMID: 35625880]
[110]
Olufunmilayo, E.O.; Duncan, G.M.B.; Holsinger, R.M.D. Oxidative stress and antioxidants in neurodegenerative disorders. Antioxidants, 2023, 12(2), 517.
[http://dx.doi.org/10.3390/antiox12020517] [PMID: 36830075]
[111]
Ge, L.; Liu, S.; Rubin, L.; Lazarovici, P.; Zheng, W. Research progress on neuroprotection of insulin-like growth factor-1 towards glutamate-induced neurotoxicity. Cells, 2022, 11(4), 666.
[http://dx.doi.org/10.3390/cells11040666] [PMID: 35203315]
[112]
Mykicki, N.; Herrmann, A.M.; Schwab, N.; Deenen, R.; Sparwasser, T.; Limmer, A.; Wachsmuth, L.; Klotz, L.; Köhrer, K.; Faber, C.; Wiendl, H.; Luger, T.A.; Meuth, S.G.; Loser, K. Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease. Sci. Transl. Med., 2016, 8(362), 362ra146.
[http://dx.doi.org/10.1126/scitranslmed.aaf8732] [PMID: 27797962]
[113]
Li, C.; Wu, X.; Liu, S.; Zhao, Y.; Zhu, J.; Liu, K. Roles of neuropeptide Y in neurodegenerative and neuroimmune diseases. Front. Neurosci., 2019, 13, 869.
[http://dx.doi.org/10.3389/fnins.2019.00869] [PMID: 31481869]
[114]
Wang, Q.; Cao, F.; Wu, Y. Orexinergic system in neurodegenerative diseases. Front. Aging Neurosci., 2021, 13, 713201.
[http://dx.doi.org/10.3389/fnagi.2021.713201] [PMID: 34483883]
[115]
Liguz-Lecznar, M.; Dobrzanski, G.; Kossut, M. Somatostatin and somatostatin-containing interneurons—From plasticity to pathology. Biomolecules, 2022, 12(2), 312.
[http://dx.doi.org/10.3390/biom12020312] [PMID: 35204812]
[116]
Lundström, L.; Elmquist, A.; Bartfai, T.; Langel, Ü. Galanin and its receptors in neurological disorders. Neuromolecular Med., 2005, 7(1-2), 157-180.
[http://dx.doi.org/10.1385/NMM:7:1-2:157] [PMID: 16052044]
[117]
Delgado, M.; Ganea, D. Vasoactive intestinal peptide: A neuropeptide with pleiotropic immune functions. Amino Acids, 2013, 45(1), 25-39.
[http://dx.doi.org/10.1007/s00726-011-1184-8] [PMID: 22139413]
[118]
Maasz, G.; Zrinyi, Z.; Reglodi, D.; Petrovics, D.; Rivnyak, A.; Kiss, T.; Jungling, A.; Tamas, A.; Pirger, Z. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models. Dis. Model. Mech., 2017, 10(2), 127-139.
[PMID: 28067625]
[119]
Frago, L.; Baquedano, E.; Argente, J.; Chowen, J.A. Neuroprotective actions of ghrelin and growth hormone secretagogues. Front. Mol. Neurosci., 2011, 4, 23.
[http://dx.doi.org/10.3389/fnmol.2011.00023] [PMID: 21994488]
[120]
Signore, A.P.; Zhang, F.; Weng, Z.; Gao, Y.Q.; Chen, J. Leptin neuroprotection in the central nervous system: Mechanisms and therapeutic potentials. J. Neurochem., 2008, 106(5), 1977.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05457.x] [PMID: 18466320]
[121]
Carson, M.J.; Thrash, C.J.; Walter, B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin. Neurosci. Res., 2006, 6(5), 237-245.
[http://dx.doi.org/10.1016/j.cnr.2006.09.004] [PMID: 19169437]
[122]
Glass, C.K.; Saijo, K.; Winner, B.; Marchetto, M.C.; Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell, 2010, 140(6), 918-934.
[http://dx.doi.org/10.1016/j.cell.2010.02.016] [PMID: 20303880]
[123]
Johnson, H.J.; Koshy, A.A. Understanding neuroinflammation through central nervous system infections. Curr. Opin. Neurobiol., 2022, 76, 102619.
[http://dx.doi.org/10.1016/j.conb.2022.102619] [PMID: 35985075]
[124]
Li, D.; Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther., 2021, 6(1), 291.
[http://dx.doi.org/10.1038/s41392-021-00687-0] [PMID: 34344870]
[125]
Lee, YS; Jun, HS Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm., 2016, 2016
[126]
Gokhale, A.S.; Satyanarayanajois, S. Peptides and peptidomimetics as immunomodulators. Immunotherapy, 2014, 6(6), 755-774.
[http://dx.doi.org/10.2217/imt.14.37] [PMID: 25186605]
[127]
Roux, P.P.; Blenis, J. ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev., 2004, 68(2), 320-344.
[http://dx.doi.org/10.1128/MMBR.68.2.320-344.2004] [PMID: 15187187]
[128]
Zhang, T.; Ma, C.; Zhang, Z.; Zhang, H.; Hu, H. NF-κB signaling in inflammation and cancer. MedComm., 2021, 2(4), 618-653.
[http://dx.doi.org/10.1002/mco2.104] [PMID: 34977871]
[129]
Boldin, R.; Zychar, B.C.; Gonçalves, L.R.C.; Sciani, J.M. Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1. Front. Pharmacol., 2023, 14, 1184006.
[http://dx.doi.org/10.3389/fphar.2023.1184006] [PMID: 37397495]
[130]
Peighambardoust, S.H.; Karami, Z.; Pateiro, M.; Lorenzo, J.M. A review on health-promoting, biological, and functional aspects of bioactive peptides in food applications. Biomolecules, 2021, 11(5), 631.
[http://dx.doi.org/10.3390/biom11050631] [PMID: 33922830]
[131]
Angeloni, C.; Malaguti, M.; Prata, C.; Freschi, M.; Barbalace, M.; Hrelia, S. Mechanisms underlying neurodegenerative disorders and potential neuroprotective activity of agrifood by-products. Antioxidants, 2022, 12(1), 94.
[http://dx.doi.org/10.3390/antiox12010094] [PMID: 36670956]
[132]
Uttara, B.; Singh, A.; Zamboni, P.; Mahajan, R. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Curr. Neuropharmacol., 2009, 7(1), 65-74.
[http://dx.doi.org/10.2174/157015909787602823] [PMID: 19721819]
[133]
Jeremic, D.; Díaz, J.L.; López, N.J.D. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: A systematic review. Ageing Res. Rev., 2021, 72, 101496.
[http://dx.doi.org/10.1016/j.arr.2021.101496] [PMID: 34687956]
[134]
Kour, A.; Dube, T.; Kumar, A.; Panda, J.J. Anti-amyloidogenic and fibril-disaggregating potency of the levodopa-functionalized gold nanoroses as exemplified in a diphenylalanine-based amyloid model. Bioconjug. Chem., 2022, 33(2), 397-410.
[http://dx.doi.org/10.1021/acs.bioconjchem.2c00007] [PMID: 35120290]
[135]
Wang, R.; Zhang, Y.; Guo, Y.; Zeng, W.; Li, J.; Wu, J. Plant-derived nanovesicles: Promising therapeutics and drug delivery nanoplatforms for brain disorders. In: Fundamental Research; , 2023.
[136]
Pajares, M.; I Rojo, A.; Manda, G.; Boscá, L.; Cuadrado, A. Inflammation in parkinson’s disease: Mechanisms and therapeutic implications. Cells, 2020, 9(7), 1687.
[http://dx.doi.org/10.3390/cells9071687] [PMID: 32674367]
[137]
Valadão, P.A.C.; Santos, K.B.S.; Vieira, F.T.H.; e Cordeiro, M.T.; Teixeira, A.L.; Guatimosim, C.; De Miranda, A.S. Inflammation in Huntington’s disease: A few new twists on an old tale. J. Neuroimmunol., 2020, 348, 577380.
[http://dx.doi.org/10.1016/j.jneuroim.2020.577380] [PMID: 32896821]
[138]
Calderón, T.P.A.; Chinchilla, V.C.D.; Lara, G.S. Natural peptides inducing cancer cell death: Mechanisms and properties of specific candidates for cancer therapeutics. Molecules, 2021, 26(24), 7453.
[http://dx.doi.org/10.3390/molecules26247453] [PMID: 34946535]
[139]
Wu, S.; Bekhit, A.E.D.A.; Wu, Q.; Chen, M.; Liao, X.; Wang, J.; Ding, Y. Bioactive peptides and gut microbiota: Candidates for a novel strategy for reduction and control of neurodegenerative diseases. Trends Food Sci. Technol., 2021, 108, 164-176.
[http://dx.doi.org/10.1016/j.tifs.2020.12.019]
[140]
Cicero, A.F.G.; Fogacci, F.; Colletti, A. Potential role of bioactive peptides in prevention and treatment of chronic diseases: A narrative review. Br. J. Pharmacol., 2017, 174(11), 1378-1394.
[http://dx.doi.org/10.1111/bph.13608] [PMID: 27572703]
[141]
Wang, J.; Wu, Y.; Chen, Z.; Chen, Y.; Lin, Q.; Liang, Y. Exogenous bioactive peptides have a potential therapeutic role in delaying aging in rodent models. Int. J. Mol. Sci., 2022, 23(3), 1421.
[http://dx.doi.org/10.3390/ijms23031421] [PMID: 35163342]
[142]
Balakrishnan, R.; Cho, D.Y.; Kim, I.S.; Seol, S.H.; Choi, D.K. Molecular mechanisms and therapeutic potential of α- and β-asarone in the treatment of neurological disorders. Antioxidants, 2022, 11(2), 281.
[http://dx.doi.org/10.3390/antiox11020281] [PMID: 35204164]
[143]
Cardoso, M.H.; Orozco, R.Q.; Rezende, S.B.; Rodrigues, G.; Oshiro, K.G.N.; Cândido, E.S.; Franco, O.L. Computer-aided design of antimicrobial peptides: Are we generating effective drug candidates? Front. Microbiol., 2020, 10, 3097.
[http://dx.doi.org/10.3389/fmicb.2019.03097] [PMID: 32038544]
[144]
Moir, R.D.; Lathe, R.; Tanzi, R.E. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement., 2018, 14(12), 1602-1614.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3040] [PMID: 30314800]
[145]
Hollmann, A.; Martinez, M.; Maturana, P.; Semorile, L.C.; Maffia, P.C. Antimicrobial peptides: interaction with model and biological membranes and synergism with chemical antibiotics. Front Chem., 2018, 6, 204.
[http://dx.doi.org/10.3389/fchem.2018.00204] [PMID: 29922648]
[146]
Lee, E.Y.; Chan, L.C.; Wang, H.; Lieng, J.; Hung, M.; Srinivasan, Y.; Wang, J.; Waschek, J.A.; Ferguson, A.L.; Lee, K.F.; Yount, N.Y.; Yeaman, M.R.; Wong, G.C.L. PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain. Proc. Natl. Acad. Sci., 2021, 118(1), e1917623117.
[http://dx.doi.org/10.1073/pnas.1917623117] [PMID: 33372152]
[147]
Toda, H.; Williams, J.A.; Gulledge, M.; Sehgal, A. A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila. Science, 2019, 363(6426), 509-515.
[http://dx.doi.org/10.1126/science.aat1650] [PMID: 30705188]
[148]
Augustin, R.; Schröder, K.; Rincón, M.A.P.; Fraune, S.; Erxleben, A.F.; Herbst, E.M.; Wittlieb, J.; Schwentner, M.; Grötzinger, J.; Wassenaar, T.M.; Bosch, T.C.G. A secreted antibacterial neuropeptide shapes the microbiome of Hydra. Nat. Commun., 2017, 8(1), 698.
[http://dx.doi.org/10.1038/s41467-017-00625-1] [PMID: 28951596]
[149]
Barajas-Azpeleta, R.; Wu, J.; Gill, J.; Welte, R.; Seidel, C.; McKinney, S.; Dissel, S.; Si, K. Antimicrobial peptides modulate long-term memory. PLoS Genet., 2018, 14(10), e1007440.
[http://dx.doi.org/10.1371/journal.pgen.1007440] [PMID: 30312294]
[150]
Guaní-Guerra, E.; Santos-Mendoza, T.; Lugo-Reyes, S.O.; Terán, L.M. Antimicrobial peptides: General overview and clinical implications in human health and disease. Clin. Immunol., 2010, 135(1), 1-11.
[http://dx.doi.org/10.1016/j.clim.2009.12.004] [PMID: 20116332]
[151]
Hanson, M.A.; Lemaitre, B. New insights on drosophila antimicrobial peptide function in host defense and beyond. Curr. Opin. Immunol., 2020, 62, 22-30.
[http://dx.doi.org/10.1016/j.coi.2019.11.008] [PMID: 31835066]
[152]
Swanson, L.C.; Rimkus, S.A.; Ganetzky, B.; Wassarman, D.A. Loss of the antimicrobial peptide metchnikowin protects against traumatic brain injury outcomes in Drosophila melanogaster. G3: Genes, Genomes. Genetics, 2020, 10(9), 3109-3119.
[http://dx.doi.org/10.1534/g3.120.401377] [PMID: 32631949]
[153]
Maezawa, I.; Zimin, P.I.; Wulff, H.; Jin, L.W. Amyloid-β protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J. Biol. Chem., 2011, 286(5), 3693-3706.
[http://dx.doi.org/10.1074/jbc.M110.135244] [PMID: 20971854]
[154]
Schröder, N.; Schaffrath, A.; Welter, J.A.; Putzka, T.; Griep, A.; Ziegler, P.; Brandt, E.; Samer, S.; Heneka, M.T.; Kaddatz, H.; Zhan, J.; Kipp, E.; Pufe, T.; Tauber, S.C.; Kipp, M.; Brandenburg, L.O. Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease. J. Neuroinflammation, 2020, 17(1), 131.
[http://dx.doi.org/10.1186/s12974-020-01816-2] [PMID: 32331524]
[155]
De Lorenzi, E.; Chiari, M.; Colombo, R.; Cretich, M.; Sola, L.; Vanna, R.; Gagni, P.; Bisceglia, F.; Morasso, C.; Lin, J.S.; Lee, M.; McGeer, P.L.; Barron, A.E. Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly. J. Alzheimers Dis., 2017, 59(4), 1213-1226.
[http://dx.doi.org/10.3233/JAD-170223] [PMID: 28731438]
[156]
Beatman, E.L.; Massey, A.; Shives, K.D.; Burrack, K.S.; Chamanian, M.; Morrison, T.E.; Beckham, J.D. Alpha-synuclein expression restricts RNA viral infections in the brain. J. Virol., 2016, 90(6), 2767-2782.
[http://dx.doi.org/10.1128/JVI.02949-15] [PMID: 26719256]
[157]
Kounatidis, I.; Chtarbanova, S.; Cao, Y.; Hayne, M.; Jayanth, D.; Ganetzky, B.; Ligoxygakis, P. NF-κB immunity in the brain determines fly lifespan in healthy aging and age-related neurodegeneration. Cell Rep., 2017, 19(4), 836-848.
[http://dx.doi.org/10.1016/j.celrep.2017.04.007] [PMID: 28445733]
[158]
AlMatar, M.; Albarri, O.; lakhal, R.; Ocal, M.M.; Var, I.; Köksal, F. Bacterial pathogens: Potential source for antimicrobial peptides. Curr. Protein Pept. Sci., 2023, 24(7), 551-566.
[http://dx.doi.org/10.2174/1389203724666230726100303] [PMID: 37496250]
[159]
E., Lazi; Zhou, T.; Koh, S.; Chuang, M.; Sharma, R.; Pujol, N.; Chisholm, A.D.; Eroglu, C.; Matsunami, H.; Yan, D. An antimicrobial peptide and its neuronal receptor regulate dendrite degeneration in aging and infection. Neuron, 2018, 97(1), 125-138.e5.
[http://dx.doi.org/10.1016/j.neuron.2017.12.001] [PMID: 29301098]
[160]
AlMatar, M.; Makky, E.A.; Yakıcı, G.; Var, I.; Kayar, B.; Köksal, F. Antimicrobial peptides as an alternative to anti-tuberculosis drugs. Pharmacol. Res., 2018, 128, 288-305.
[http://dx.doi.org/10.1016/j.phrs.2017.10.011] [PMID: 29079429]
[161]
Erkkinen, M.G.; Kim, M.O.; Geschwind, M.D. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb. Perspect. Biol., 2018, 10(4), a033118.
[http://dx.doi.org/10.1101/cshperspect.a033118] [PMID: 28716886]
[162]
Zhao, L.; Li, D.; Qi, X.; Guan, K.; Chen, H.; Wang, R.; Ma, Y. Potential of food-derived bioactive peptides in alleviation and prevention of Alzheimer’s disease. Food Funct., 2022, 13(21), 10851-10869.
[http://dx.doi.org/10.1039/D2FO02278H] [PMID: 36219143]
[163]
Siafaka, P.I.; Okur, M.E.; Erim, P.D.; Çağlar, E.Ş.; Özgenç, E.; Gündoğdu, E.; Köprülü, R.E.P.; Karantas, I.D.; Okur, U.N. Protein and gene delivery systems for neurodegenerative disorders: Where do we stand today? Pharmaceutics, 2022, 14(11), 2425.
[http://dx.doi.org/10.3390/pharmaceutics14112425] [PMID: 36365243]
[164]
Bhattacharya, T.; Soares, G.A.B.; Chopra, H.; Rahman, M.M.; Hasan, Z.; Swain, S.S.; Cavalu, S. Applications of phyto-nanotechnology for the treatment of neurodegenerative disorders. Materials, 2022, 15(3), 804.
[http://dx.doi.org/10.3390/ma15030804] [PMID: 35160749]
[165]
Arafah, A.; Khatoon, S.; Rasool, I.; Khan, A.; Rather, M.A.; Abujabal, K.A.; Faqih, Y.A.H.; Rashid, H.; Rashid, S.M.; Ahmad, B.S.; Alexiou, A.; Rehman, M.U. The future of precision medicine in the cure of alzheimer’s disease. Biomedicines, 2023, 11(2), 335.
[http://dx.doi.org/10.3390/biomedicines11020335] [PMID: 36830872]
[166]
Nayab, D.E.; Din, F.; Ali, H.; Kausar, W.A.; Urooj, S.; Zafar, M.; Khan, I.; Shabbir, K.; Khan, G.M. Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: An up-to-date perspective. J. Nanobiotechnology, 2023, 21(1), 477.
[http://dx.doi.org/10.1186/s12951-023-02250-1] [PMID: 38087359]
[167]
Nguyen, T.T.; Dung Nguyen, T.T.; Vo, T.K.; Tran, N.M.A.; Nguyen, M.K.; Van Vo, T.; Van Vo, G. Nanotechnology-based drug delivery for central nervous system disorders. Biomed. Pharmacother., 2021, 143, 112117.
[http://dx.doi.org/10.1016/j.biopha.2021.112117] [PMID: 34479020]
[168]
Dedeoglu, A.; Kubilus, J.K.; Yang, L.; Ferrante, K.L.; Hersch, S.M.; Beal, M.F.; Ferrante, A.R.J. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J. Neurochem., 2003, 85(6), 1359-1367.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01706.x] [PMID: 12787055]
[169]
Ezaki, M.; Baek, G.H.; Horii, E.; Hovius, S. IFSSH scientific committee on congenital conditions. J. Hand Surg. Eur. Vol., 2014, 39(6), 676-678.
[http://dx.doi.org/10.1177/1753193414526334] [PMID: 24939554]
[170]
Kasatkina, L.A.; Rittchen, S.; Sturm, E.M. Neuroprotective and immunomodulatory action of the endocannabinoid system under neuroinflammation. Int. J. Mol. Sci., 2021, 22(11), 5431.
[http://dx.doi.org/10.3390/ijms22115431] [PMID: 34063947]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version512msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[17:07:43] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[17:07:43] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[17:07:43] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[17:07:43] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (148ms)time
  • Application (364ms)time
  • 1 x Application (71.11%)
    364ms
    1 x Booting (28.89%)
    148ms
    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 duplicated236ms
    • 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 ('316312588','',1,1740676063,1740676063) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740676063
      8.05msalphaeurekaselec_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 ('316312588','/article/139453',1,1740676063,1740676063)
      10.69msalphaeurekaselec_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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) 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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) 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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) 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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) 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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) 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 >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316312588 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316312588) limit 1
      68.96msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316312588
      • 1: 316312588
      • 2: 316312588
      • 3: 316312588
      • 4: 316312588
      • 5: 316312588
      • 6: 316312588
      • 7: 316312588
      • 8: 316312588
      • 9: 316312588
      • 10: 316312588
      • 11: 316312588
      • 12: 316312588
      • 13: 316312588
      • 14: 316312588
      • 15: 316312588
      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=139453
      3.39msalphaeurekaselec_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` = 42 limit 1
      1.11msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 42
      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=42) and sj.journal_id!=42 group by `j`.`nid`) as `aggregate_table`
      1.18msalphaeurekaselec_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=42) and sj.journal_id!=42 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      5.35msalphaeurekaselec_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=42) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      4.45msalphaeurekaselec_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=42) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      3.54msalphaeurekaselec_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` = '139453'
      350μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 139453
      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` = '139453'
      5.5msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 139453
      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` = '139453' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.66msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 139453
      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
      370μsalphaeurekaselec_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
      760μsalphaeurekaselec_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 = 42 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      46.64msalphaeurekaselec_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 = 42 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      13.36msalphaeurekaselec_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 = 42 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      13.56msalphaeurekaselec_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` = 139453 limit 1
      280μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 139453
      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 = 139453 and content_type = 'article' order by status desc limit 1
      410μsalphaeurekaselec_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` = 228450 limit 1
      300μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 228450
      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
      340μsalphaeurekaselec_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` = 'CPPS' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      580μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CPPS
      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 = '139453' 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) )
      580μsalphaeurekaselec_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 = '13415' 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 = '3503' 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) )
      440μsalphaeurekaselec_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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3503) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3503) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3503)
      30.6msalphaeurekaselec_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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13415) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13415) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13415)
      1.01msalphaeurekaselec_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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 139453) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 139453) 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 <= 316312588 and j.to_ip >=316312588 )) and ((j.from_date <= 1740676063 and j.to_date >= 1740676063 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 139453)
      920μsalphaeurekaselec_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` < '507' and is_uploaded = 1 and issue_id = 13415 order by cast(first_page as SIGNED) desc limit 1
      750μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 507
      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` > '526' and is_uploaded = 1 and issue_id = 13415 order by cast(first_page as SIGNED) asc limit 1
      630μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 526
      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
      370μsalphaeurekaselec_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` = 139453 limit 1
      3.9msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 139453
      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` = 42 and `b`.`banner_from_date` <= 1740676063 and `b`.`banner_to_date` >= 1740676063 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.9msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 42
      • 3: 1740676063
      • 4: 1740676063
      • 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` = 42 and `b`.`banner_from_date` <= 1740676063 and `b`.`banner_to_date` >= 1740676063 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.68msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 42
      • 3: 1740676063
      • 4: 1740676063
      • 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='76577939f5d989d66024da1b647b88ac'
      370μsalphaeurekaselec_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
        IRzW8ciszEOSq5aUcoT48hqpBH38P9LzHc7kPOjp
        uc_cart_id
        76577939f5d989d66024da1b647b88ac
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/139453" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/139453
        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 => "Thu, 27 Feb 2025 17:07:43 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlQ5N3NIeS8yZ1ZMQmJvYWRBRm93Nmc9PSIsInZhbHVlIjoidmtSbnA0SU16SEIwV3FTYi9VbXFIcE95cGQ0RHZjK0xJb3Fmdzd4S0pMeFVWaUlWbG8veHFDQWVYT3FqV3BUSVN0NUJzeHliMDA5QStBMkdYNmpNZ2FzN25WZ3d3bE0yaUZOWnRtdWtpUUxSQ2N1T1ZmKzZCWGRFOE1JWDZCYVYiLCJtYWMiOiI1Njk2NjJlZjgzMTQ1ZDY2YjRhNTM1Y2Q0ZDdkYmFhMTM3NjZhZTllYzEwNjZhMzkyNTg1Nzk2YTA1MTdiMzg1IiwidGFnIjoiIn0%3D; expires=Sun, 02 Mar 2025 05:07:43 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlQ5N3NIeS8yZ1ZMQmJvYWRBRm93Nmc9PSIsInZhbHVlIjoidmtSbnA0SU16SEIwV3FTYi9VbXFIcE95cGQ0RHZjK0xJb3Fmdzd4S0pMeFVWaUlWbG8veHFDQWVYT3FqV3BUSVN0NUJze" 1 => "alphaeurekaselectnet_session=eyJpdiI6InluV0MwTEZqREhaOEFUV2d3TS8xNXc9PSIsInZhbHVlIjoiN295TThTc0lyNVBMcGg1TE5uelNXM0ZqUHEzNXRUWll5UmpXb2ZHQjBkR3drSE16NzZoQUNOcjUxL1I4cW9qUWZGK3owVXlpcTlCWEg1a2Q0K2V6Wmx2ZHlLaG5yNWg0bldDSVBEazZVT2ZvZzFzSkRXUlFsSjE5RVZ0THhvVUUiLCJtYWMiOiIyOWZhMDkwYTg3NGU5OWM2M2RlOWUyZDZlYjc4Zjg1MDg4MTNmMGRkZjEzNzk4OTU2ZjcxYTc0OTczM2UxNDY4IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InluV0MwTEZqREhaOEFUV2d3TS8xNXc9PSIsInZhbHVlIjoiN295TThTc0lyNVBMcGg1TE5uelNXM0ZqUHEzNXRUWll5UmpXb2ZHQjBkR3drSE16NzZoQUNOcjU" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlQ5N3NIeS8yZ1ZMQmJvYWRBRm93Nmc9PSIsInZhbHVlIjoidmtSbnA0SU16SEIwV3FTYi9VbXFIcE95cGQ0RHZjK0xJb3Fmdzd4S0pMeFVWaUlWbG8veHFDQWVYT3FqV3BUSVN0NUJzeHliMDA5QStBMkdYNmpNZ2FzN25WZ3d3bE0yaUZOWnRtdWtpUUxSQ2N1T1ZmKzZCWGRFOE1JWDZCYVYiLCJtYWMiOiI1Njk2NjJlZjgzMTQ1ZDY2YjRhNTM1Y2Q0ZDdkYmFhMTM3NjZhZTllYzEwNjZhMzkyNTg1Nzk2YTA1MTdiMzg1IiwidGFnIjoiIn0%3D; expires=Sun, 02-Mar-2025 05:07:43 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlQ5N3NIeS8yZ1ZMQmJvYWRBRm93Nmc9PSIsInZhbHVlIjoidmtSbnA0SU16SEIwV3FTYi9VbXFIcE95cGQ0RHZjK0xJb3Fmdzd4S0pMeFVWaUlWbG8veHFDQWVYT3FqV3BUSVN0NUJze" 1 => "alphaeurekaselectnet_session=eyJpdiI6InluV0MwTEZqREhaOEFUV2d3TS8xNXc9PSIsInZhbHVlIjoiN295TThTc0lyNVBMcGg1TE5uelNXM0ZqUHEzNXRUWll5UmpXb2ZHQjBkR3drSE16NzZoQUNOcjUxL1I4cW9qUWZGK3owVXlpcTlCWEg1a2Q0K2V6Wmx2ZHlLaG5yNWg0bldDSVBEazZVT2ZvZzFzSkRXUlFsSjE5RVZ0THhvVUUiLCJtYWMiOiIyOWZhMDkwYTg3NGU5OWM2M2RlOWUyZDZlYjc4Zjg1MDg4MTNmMGRkZjEzNzk4OTU2ZjcxYTc0OTczM2UxNDY4IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InluV0MwTEZqREhaOEFUV2d3TS8xNXc9PSIsInZhbHVlIjoiN295TThTc0lyNVBMcGg1TE5uelNXM0ZqUHEzNXRUWll5UmpXb2ZHQjBkR3drSE16NzZoQUNOcjU" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "IRzW8ciszEOSq5aUcoT48hqpBH38P9LzHc7kPOjp" "uc_cart_id" => "76577939f5d989d66024da1b647b88ac" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/139453" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-27 17:07:43GET/article/139453414361