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Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Review Article

Natural Product-based Nanomedicine: Recent Advances and Issues for the Treatment of Alzheimer's Disease

Author(s): Choy Ker Woon, Wong Kah Hui , Razif Abas, Muhammad Huzaimi Haron , Srijit Das and Teoh Seong Lin *

Volume 20, Issue 8, 2022

Published on: 25 March, 2022

Page: [1498 - 1518] Pages: 21

DOI: 10.2174/1570159X20666211217163540

Price: $65

Abstract

Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and their severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano-sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material's bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicinebased approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.

Keywords: Alzheimer’s disease, amyloid-β, nanoparticles, blood-brain barrier, phytochemicals, drug delivery.

Graphical Abstract

[1]
Weller, J.; Budson, A. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000 Res., 2018, 7, 1161.
[http://dx.doi.org/10.12688/f1000research.14506.1] [PMID: 30135715]
[2]
Mohsen, H.; El-Dahshan, E-S.A.; El-Horbaty, E-S.M.; Salem, A-B.M. Classification of brain MRI for Alzheimer’s disease based on linear discriminate analysis. Egyptian Comput Sci J, 2017, 41(3), 44-52.
[3]
Prince, M.; Wimo, A.; Guerchet, M.; Ali, G.C.; Wu, Y.T.; Prina, M. The global impact of dementia: An analysis of prevalence, incidence, cost and trends. 2015, 2015
[4]
Koedam, E.L.; Lauffer, V.; van der Vlies, A.E.; van der Flier, W.M.; Scheltens, P.; Pijnenburg, Y.A. Early-versus late-onset Alzheimer’s disease: more than age alone. J. Alzheimers Dis., 2010, 19(4), 1401-1408.
[http://dx.doi.org/10.3233/JAD-2010-1337] [PMID: 20061618]
[5]
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[6]
Guo, T.; Zhang, D.; Zeng, Y.; Huang, T.Y.; Xu, H.; Zhao, Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol. Neurodegener., 2020, 15(1), 40.
[http://dx.doi.org/10.1186/s13024-020-00391-7] [PMID: 32677986]
[7]
Chen, X.Q.; Mobley, W.C. Alzheimer disease pathogenesis: Insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front. Neurosci., 2019, 13, 659.
[http://dx.doi.org/10.3389/fnins.2019.00659] [PMID: 31293377]
[8]
Montagne, A.; Nation, D.A.; Pa, J.; Sweeney, M.D.; Toga, A.W.; Zlokovic, B.V. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol., 2016, 131(5), 687-707.
[http://dx.doi.org/10.1007/s00401-016-1570-0] [PMID: 27038189]
[9]
Miners, J.S.; Kehoe, P.G.; Love, S.; Zetterberg, H.; Blennow, K. CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology. Alzheimers Res. Ther., 2019, 11(1), 81.
[http://dx.doi.org/10.1186/s13195-019-0534-8] [PMID: 31521199]
[10]
Pasha, S.; Gupta, K. Various drug delivery approaches to the central nervous system. Expert Opin. Drug Deliv., 2010, 7(1), 113-135.
[http://dx.doi.org/10.1517/17425240903405581] [PMID: 20017662]
[11]
Montagne, A.; Zhao, Z.; Zlokovic, B.V. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J. Exp. Med., 2017, 214(11), 3151-3169.
[http://dx.doi.org/10.1084/jem.20171406] [PMID: 29061693]
[12]
Zhao, Z.; Nelson, A.R.; Betsholtz, C.; Zlokovic, B.V. Establishment and dysfunction of the blood-brain barrier. Cell, 2015, 163(5), 1064-1078.
[http://dx.doi.org/10.1016/j.cell.2015.10.067] [PMID: 26590417]
[13]
Do, T.M.; Dodacki, A.; Alata, W.; Calon, F.; Nicolic, S.; Scherrmann, J.M.; Farinotti, R.; Bourasset, F. Age-dependent regulation of the blood-brain barrier influx/efflux equilibrium of amyloid-β peptide in a mouse model of Alzheimer’s disease (3xTg-AD). J. Alzheimers Dis., 2016, 49(2), 287-300.
[http://dx.doi.org/10.3233/JAD-150350] [PMID: 26484906]
[14]
Winkler, E.A.; Nishida, Y.; Sagare, A.P.; Rege, S.V.; Bell, R.D.; Perlmutter, D.; Sengillo, J.D.; Hillman, S.; Kong, P.; Nelson, A.R.; Sullivan, J.S.; Zhao, Z.; Meiselman, H.J.; Wendy, R.B.; Soto, J.; Abel, E.D.; Makshanoff, J.; Zuniga, E.; De Vivo, D.C.; Zlokovic, B.V. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci., 2015, 18(4), 521-530.
[http://dx.doi.org/10.1038/nn.3966] [PMID: 25730668]
[15]
Du, X.; Wang, X.; Geng, M. Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener., 2018, 7(1), 2.
[http://dx.doi.org/10.1186/s40035-018-0107-y] [PMID: 29423193]
[16]
Husna Ibrahim, N.; Yahaya, M.F.; Mohamed, W.; Teoh, S.L.; Hui, C.K.; Kumar, J. Pharmacotherapy of Alzheimer’s Disease: Seeking Clarity in a Time of Uncertainty. Front. Pharmacol., 2020, 11, 261.
[http://dx.doi.org/10.3389/fphar.2020.00261] [PMID: 32265696]
[17]
Qaseem, A.; Snow, V.; Cross, J.T., Jr; Forciea, M.A.; Hopkins, R., Jr; Shekelle, P.; Adelman, A.; Mehr, D.; Schellhase, K.; Campos-Outcalt, D.; Santaguida, P.; Owens, D.K. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann. Intern. Med., 2008, 148(5), 370-378.
[http://dx.doi.org/10.7326/0003-4819-148-5-200803040-00008] [PMID: 18316755]
[18]
Ayaz, M.; Junaid, M.; Ullah, F.; Sadiq, A.; Khan, M.A.; Ahmad, W.; Shah, M.R.; Imran, M.; Ahmad, S. Comparative chemical profiling, cholinesterase inhibitions and anti-radicals properties of essential oils from Polygonum hydropiper L: a preliminary anti- Alzheimer’s study. Lipids Health Dis., 2015, 14, 141.
[http://dx.doi.org/10.1186/s12944-015-0145-8] [PMID: 26530857]
[19]
Nisticò, R.; Borg, J.J. Aducanumab for Alzheimer’s disease: A regulatory perspective. Pharmacol. Res., 2021, 171, 105754.
[http://dx.doi.org/10.1016/j.phrs.2021.105754] [PMID: 34217830]
[20]
Walsh, S.; Merrick, R.; Milne, R.; Brayne, C. Aducanumab for Alzheimer’s disease? BMJ, 2021, 374, n1682.
[http://dx.doi.org/10.1136/bmj.n1682] [PMID: 34226181]
[21]
Birks, J.S.; Harvey, R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst. Rev., 2003, (3), CD001190.
[http://dx.doi.org/10.1002/14651858.Cd001190(3)] [PMID: 12917900]
[22]
Casey, D.A.; Antimisiaris, D.; O'Brien, J. Drugs for Alzheimer's disease: are they effective? P T., 2010, 35(4), 208-211.
[PMID: 20498822]
[23]
Blanco-Silvente, L.; Castells, X.; Saez, M.; Barceló, M.A.; Garre-Olmo, J.; Vilalta-Franch, J.; Capellà, D. Discontinuation, efficacy, and safety of cholinesterase inhibitors for Alzheimer’s disease: A meta-analysis and meta-regression of 43 randomized clinical trials enrolling 16 106 patients. Int. J. Neuropsychopharmacol., 2017, 20(7), 519-528.
[http://dx.doi.org/10.1093/ijnp/pyx012] [PMID: 28201726]
[24]
Tan, C.C.; Yu, J.T.; Wang, H.F.; Tan, M.S.; Meng, X.F.; Wang, C.; Jiang, T.; Zhu, X.C.; Tan, L. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. J. Alzheimers Dis., 2014, 41(2), 615-631.
[http://dx.doi.org/10.3233/JAD-132690] [PMID: 24662102]
[25]
Matsunaga, S.; Kishi, T.; Nomura, I.; Sakuma, K.; Okuya, M.; Ikuta, T.; Iwata, N. The efficacy and safety of memantine for the treatment of Alzheimer’s disease. Expert Opin. Drug Saf., 2018, 17(10), 1053-1061.
[http://dx.doi.org/10.1080/14740338.2018.1524870] [PMID: 30222469]
[26]
Philomena, G. Concerns regarding the safety and toxicity of medicinal plants - An overview. J. Appl. Pharm. Sci., 2011, 1(6), 40-44.
[27]
Karimi, A.; Majlesi, M.; Rafieian-Kopaei, M. Herbal versus synthetic drugs; beliefs and facts. J. Nephropharmacol., 2015, 4(1), 27-30.
[PMID: 28197471]
[28]
Cheung, T.S.; Song, T.H.; Ng, T.B.; Wu, F.H.; Lao, L.X.; Tang, S.C.; Ho, J.C.; Zhang, K.Y.; Sze, S.C. Therapeutic effects of herbal chemicals in traditional chinese medicine on Alzheimer’s disease. Curr. Med. Chem., 2015, 22(19), 2392-2403.
[http://dx.doi.org/10.2174/0929867322666150520095509] [PMID: 25989911]
[29]
Long, F.; Yang, H.; Xu, Y.; Hao, H.; Li, P. A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines. Sci. Rep., 2015, 5, 12361.
[http://dx.doi.org/10.1038/srep12361] [PMID: 26198093]
[30]
Engelborghs, S.; Gilles, C.; Ivanoiu, A.; Vandewoude, M. Rationale and clinical data supporting nutritional intervention in Alzheimer’s disease. Acta Clin. Belg., 2014, 69(1), 17-24.
[http://dx.doi.org/10.1179/0001551213Z.0000000006] [PMID: 24635394]
[31]
Teixeira, J.; Silva, T.; Andrade, P.B.; Borges, F. Alzheimer’s disease and antioxidant therapy: how long how far? Curr. Med. Chem., 2013, 20(24), 2939-2952.
[http://dx.doi.org/10.2174/1871523011320240001] [PMID: 23409717]
[32]
Kivipelto, M.; Laakso, M.P.; Tuomilehto, J.; Nissinen, A.; Soininen, H. Hypertension and hypercholesterolaemia as risk factors for Alzheimer’s disease: potential for pharmacological intervention. CNS Drugs, 2002, 16(7), 435-444.
[http://dx.doi.org/10.2165/00023210-200216070-00001] [PMID: 12056919]
[33]
Li, M.; Guo, K.; Ikehara, S. Stem cell treatment for Alzheimer’s disease. Int. J. Mol. Sci., 2014, 15(10), 19226-19238.
[http://dx.doi.org/10.3390/ijms151019226] [PMID: 25342318]
[34]
Honjo, H.; Iwasa, K.; Fushiki, S.; Hosoda, T.; Tatsumi, H.; Mihara, M.; Hirasugi, Y.; Oida, M.; Kariya, K.; Kikuchi, N.; Kawata, M. Estrogen and non-feminizing estrogen for Alzheimer’s disease. Endocr. J., 2003, 50(4), 361-367.
[http://dx.doi.org/10.1507/endocrj.50.361] [PMID: 14599108]
[35]
Ghavami, A.; Hirst, W.D.; Novak, T.J. Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit? Drugs R D., 2006, 7(2), 63-71.
[http://dx.doi.org/10.2165/00126839-200607020-00001] [PMID: 16542053]
[36]
Sampson, E.L.; Jenagaratnam, L.; McShane, R. Metal protein attenuating compounds for the treatment of Alzheimer’s dementia. Cochrane Database Syst. Rev., 2014, CD005380(2), CD005380.
[http://dx.doi.org/10.1002/14651858.CD005380.pub5] [PMID: 24563468]
[37]
Kandimalla, R.; Reddy, P.H. Therapeutics of Neurotransmitters in Alzheimer’s Disease. J. Alzheimers Dis., 2017, 57(4), 1049-1069.
[http://dx.doi.org/10.3233/JAD-161118] [PMID: 28211810]
[38]
Wollen, K.A. Alzheimer’s disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners. Altern. Med. Rev., 2010, 15(3), 223-244.
[PMID: 21155625]
[39]
Ghosh, A.K.; Mesecar, A.; Brindisi, M.; Cardenas, E.L. Bace1 inhibitors for the treatment of Alzheimer’s disease; Google Patents, 2020.
[40]
Krishnaswamy, S.; Verdile, G.; Groth, D.; Kanyenda, L.; Martins, R.N. The structure and function of Alzheimer’s gamma secretase enzyme complex. Crit. Rev. Clin. Lab. Sci., 2009, 46(5-6), 282-301.
[http://dx.doi.org/10.3109/10408360903335821] [PMID: 19958215]
[41]
Mancuso, C.; Bates, T.E.; Butterfield, D.A.; Calafato, S.; Cornelius, C.; De Lorenzo, A.; Dinkova Kostova, A.T.; Calabrese, V. Natural antioxidants in Alzheimer’s disease. Expert Opin. Investig. Drugs, 2007, 16(12), 1921-1931.
[http://dx.doi.org/10.1517/13543784.16.12.1921] [PMID: 18042001]
[42]
Yasar, S.; Xia, J.; Yao, W.; Furberg, C.D.; Xue, Q.L.; Mercado, C.I.; Fitzpatrick, A.L.; Fried, L.P.; Kawas, C.H.; Sink, K.M.; Williamson, J.D.; DeKosky, S.T.; Carlson, M.C. Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo Evaluation of Memory Study. Neurology, 2013, 81(10), 896-903.
[http://dx.doi.org/10.1212/WNL.0b013e3182a35228] [PMID: 23911756]
[43]
Ancelin, M.L.; Carrière, I.; Barberger-Gateau, P.; Auriacombe, S.; Rouaud, O.; Fourlanos, S.; Berr, C.; Dupuy, A.M.; Ritchie, K. Lipid lowering agents, cognitive decline, and dementia: the three-city study. J. Alzheimers Dis., 2012, 30(3), 629-637.
[http://dx.doi.org/10.3233/JAD-2012-120064] [PMID: 22451317]
[44]
Lanyau-Domínguez, Y.; Macías-Matos, C.; Jesús, J.; María, G.; Suárez-Medina, R.; Eugenia, M.; Noriega-Fernández, L.; Guerra-Hernández, M.; Calvo-Rodríguez, M.; Sánchez-Gil, Y.; García-Klibanski, M.; Herrera-Javier, D.; Arocha-Oriol, C.; Díaz-Domínguez, M. Levels of vitamins and homocysteine in older adults with Alzheimer disease or mild cognitive impairment in Cuba. MEDICC Rev., 2020, 22(4), 40-47.
[http://dx.doi.org/10.37757/MR2020.V22.N4.14] [PMID: 33295319]
[45]
Dong, Y.; Chen, X.; Liu, Y.; Shu, Y.; Chen, T.; Xu, L.; Li, M.; Guan, X. Do low-serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta-analysis of case-control studies. Int. J. Geriatr. Psychiatry, 2018, 33(2), e257-e263.
[http://dx.doi.org/10.1002/gps.4780] [PMID: 28833475]
[46]
Munoz Fernandez, S.S.; Ivanauskas, T.; Lima Ribeiro, S.M. Nutritional strategies in the management of Alzheimer disease: Systematic review with network meta-analysis. J Am Med Dir Assoc, 2017, 18(10), 897.e13-897.e30.
[http://dx.doi.org/10.1016/j.jamda.2017.06.015] [PMID: 28807434]
[47]
Hu, N.; Yu, J.T.; Tan, L.; Wang, Y.L.; Sun, L.; Tan, L. Nutrition and the risk of Alzheimer’s disease. BioMed Res. Int., 2013, 2013, 524820.
[http://dx.doi.org/10.1155/2013/524820] [PMID: 23865055]
[48]
Butler, M.; Nelson, V.A.; Davila, H.; Ratner, E.; Fink, H.A.; Hemmy, L.S.; McCarten, J.R.; Barclay, T.R.; Brasure, M.; Kane, R.L. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann. Intern. Med., 2018, 168(1), 52-62.
[http://dx.doi.org/10.7326/M17-1530] [PMID: 29255909]
[49]
Forrester, L.T.; Maayan, N.; Orrell, M.; Spector, A.E.; Buchan, L.D.; Soares-Weiser, K. Aromatherapy for dementia. Cochrane Database Syst. Rev., 2014, CD003150(2), CD003150.
[http://dx.doi.org/10.1002/14651858.CD003150.pub2(2)] [PMID: 24569873]
[50]
Okuda, M.; Fujita, Y.; Takada-Takatori, Y.; Sugimoto, H.; Urakami, K. Aromatherapy improves cognitive dysfunction in senescence-accelerated mouse prone 8 by reducing the level of amyloid beta and tau phosphorylation. PLoS One, 2020, 15(10), e0240378.
[http://dx.doi.org/10.1371/journal.pone.0240378] [PMID: 33052945]
[51]
Jimbo, D.; Kimura, Y.; Taniguchi, M.; Inoue, M.; Urakami, K. Effect of aromatherapy on patients with Alzheimer’s disease. Psychogeriatrics, 2009, 9(4), 173-179.
[http://dx.doi.org/10.1111/j.1479-8301.2009.00299.x] [PMID: 20377818]
[52]
Turten Kaymaz, T.; Ozdemir, L. Effects of aromatherapy on agitation and related caregiver burden in patients with moderate to severe dementia: A pilot study. Geriatr. Nurs., 2017, 38(3), 231-237.
[http://dx.doi.org/10.1016/j.gerinurse.2016.11.001] [PMID: 27912905]
[53]
Mayeux, R.; Stern, Y. Epidemiology of Alzheimer disease. Cold Spring Harb. Perspect. Med., 2012, 2(8), a006239.
[http://dx.doi.org/10.1101/cshperspect.a006239] [PMID: 22908189]
[54]
Lee, G.; Dallas, S.; Hong, M.; Bendayan, R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol. Rev., 2001, 53(4), 569-596.
[http://dx.doi.org/10.1146/annurev.pharmtox.41.1.569] [PMID: 11734619]
[55]
Pardridge, W.M. Blood-brain barrier drug targeting: the future of brain drug development. Mol. Interv., 2003, 3(2), 90-105, 51.
[http://dx.doi.org/10.1124/mi.3.2.90] [PMID: 14993430]
[56]
Fluri, F. Clinical nanomedicine: Nanomedical approaches in Alzheimer’s disease. Eur. J. Nanomed., 2010, 3(1), 7-12.
[http://dx.doi.org/10.1515/EJNM.2010.3.1.7]
[57]
Pavan, B.; Dalpiaz, A.; Ciliberti, N.; Biondi, C.; Manfredini, S.; Vertuani, S. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules, 2008, 13(5), 1035-1065.
[http://dx.doi.org/10.3390/molecules13051035] [PMID: 18560328]
[58]
Pandit, R.; Chen, L.; Götz, J. The blood-brain barrier: Physiology and strategies for drug delivery. Adv. Drug Deliv. Rev., 2020, 165-166, 1-14.
[http://dx.doi.org/10.1016/j.addr.2019.11.009] [PMID: 31790711]
[59]
Aulić, S.; Bolognesi, M.L.; Legname, G. Small-molecule theranostic probes: a promising future in neurodegenerative diseases. Int. J. Cell Biol., 2013, 2013, 150952.
[http://dx.doi.org/10.1155/2013/150952] [PMID: 24324497]
[60]
Pohl, F.; Kong Thoo Lin, P. The potential use of plant natural products and plant extracts with antioxidant properties for the prevention/treatment of neurodegenerative diseases: In vitro, in vivo and clinical trials. Molecules, 2018, 23(12), 3283.
[http://dx.doi.org/10.3390/molecules23123283] [PMID: 30544977]
[61]
Ayaz, M.; Ullah, F.; Sadiq, A.; Kim, M.O.; Ali, T. Editorial: Natural products-based drugs: potential therapeutics against Alzheimer’s disease and other neurological disorders. Front. Pharmacol., 2019, 10, 1417.
[http://dx.doi.org/10.3389/fphar.2019.01417] [PMID: 31849668]
[62]
Phang, M.W.L.; Lew, S.Y.; Chung, I.; Lim, W.K.S.; Lim, L.W.; Wong, K.H. Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review. Chin. Med., 2021, 16(1), 15.
[http://dx.doi.org/10.1186/s13020-020-00414-x] [PMID: 33509239]
[63]
Hor, S.L.; Teoh, S.L.; Lim, W.L. Plant polyphenols as neuroprotective agents in Parkinson’s disease targeting oxidative stress. Curr. Drug Targets, 2020, 21(5), 458-476.
[http://dx.doi.org/10.2174/1389450120666191017120505] [PMID: 31625473]
[64]
World Health Organization. WHO global report on traditional and complementary medicine 2019; World Health Organization: Geneva, 2019.
[65]
Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; Habtemariam, S.; Shin, H.S. Nano based drug delivery systems: recent developments and future prospects. J. Nanobiotechnology, 2018, 16(1), 71-71.
[http://dx.doi.org/10.1186/s12951-018-0392-8] [PMID: 30231877]
[66]
Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B, 2017, 7(2), 119-136.
[http://dx.doi.org/10.1016/j.apsb.2016.06.003] [PMID: 28303218]
[67]
Harvey, A.L.; Edrada-Ebel, R.; Quinn, R.J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov., 2015, 14(2), 111-129.
[http://dx.doi.org/10.1038/nrd4510] [PMID: 25614221]
[68]
Rivero-Montejo, S.J.; Vargas-Hernandez, M.; Torres-Pacheco, I. Nanoparticles as novel elicitors to improve bioactive compounds in plants. Agriculture, 2021, 11(2), 134.
[http://dx.doi.org/10.3390/agriculture11020134]
[69]
Yuan, H.; Ma, Q.; Ye, L.; Piao, G. The traditional medicine and modern medicine from natural products. Molecules, 2016, 21(5), 559.
[http://dx.doi.org/10.3390/molecules21050559] [PMID: 27136524]
[70]
Raman, J.; Jang, K.; Lakshmanan, H. Mycosynthesis of gold nanoparticles: mechanisms and applications In: Nanobiotechnology; Ghosh, S.; Webster, T.J., Eds.; Elsevier, 2021; pp. 105-122.
[http://dx.doi.org/10.1016/B978-0-12-822878-4.00007-9]
[71]
Namdari, M.; Eatemadi, A.; Soleimaninejad, M.; Hammed, A.T. A brief review on the application of nanoparticle enclosed herbal medicine for the treatment of infective endocarditis. Biomed. Pharmacother., 2017, 87, 321-331.
[http://dx.doi.org/10.1016/j.biopha.2016.12.099] [PMID: 28064105]
[72]
Arshad, L.; Haque, M.A.; Abbas Bukhari, S.N.; Jantan, I. An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents. Future Med. Chem., 2017, 9(6), 605-626.
[http://dx.doi.org/10.4155/fmc-2016-0223] [PMID: 28394628]
[73]
Li, J.; Han, Y.; Li, M.; Nie, C. Curcumin promotes proliferation of adult neural stem cells and the birth of neurons in Alzheimer’s disease mice via notch signaling pathway. Cell. Reprogram., 2019, 21(3), 152-161.
[http://dx.doi.org/10.1089/cell.2018.0027] [PMID: 31145652]
[74]
Sun, Z.Z.; Li, X.Y.; Wang, S.; Shen, L.; Ji, H.F. Bidirectional interactions between curcumin and gut microbiota in transgenic mice with Alzheimer’s disease. Appl. Microbiol. Biotechnol., 2020, 104(8), 3507-3515.
[http://dx.doi.org/10.1007/s00253-020-10461-x] [PMID: 32095862]
[75]
Khor, P.Y.; Mohd Aluwi, M.F.F.; Rullah, K.; Lam, K.W. Insights on the synthesis of asymmetric curcumin derivatives and their biological activities. Eur. J. Med. Chem., 2019, 183, 111704.
[http://dx.doi.org/10.1016/j.ejmech.2019.111704] [PMID: 31557608]
[76]
Lee, E.H.; Lim, S.S.; Yuen, K.H.; Lee, C.Y. Curcumin and a hemi-analogue with improved blood-brain barrier permeability protect against amyloid-beta toxicity in Caenorhabditis elegans via SKN-1/Nrf activation. J. Pharm. Pharmacol., 2019, 71(5), 860-868.
[http://dx.doi.org/10.1111/jphp.13052] [PMID: 30515807]
[77]
Huang, N.; Lu, S.; Liu, X.G.; Zhu, J.; Wang, Y.J.; Liu, R.T. PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer’s disease mice. Oncotarget, 2017, 8(46), 81001-81013.
[http://dx.doi.org/10.18632/oncotarget.20944] [PMID: 29113362]
[78]
Yang, R.; Zheng, Y.; Wang, Q.; Zhao, L. Curcumin-loaded chitosan-bovine serum albumin nanoparticles potentially enhanced Aβ 42 phagocytosis and modulated macrophage polarization in Alzheimer’s disease. Nanoscale Res. Lett., 2018, 13(1), 330.
[http://dx.doi.org/10.1186/s11671-018-2759-z] [PMID: 30350003]
[79]
Barbara, R.; Belletti, D.; Pederzoli, F.; Masoni, M.; Keller, J.; Ballestrazzi, A.; Vandelli, M.A.; Tosi, G.; Grabrucker, A.M. Novel Curcumin loaded nanoparticles engineered for Blood-Brain Barrier crossing and able to disrupt Abeta aggregates. Int. J. Pharm., 2017, 526(1-2), 413-424.
[http://dx.doi.org/10.1016/j.ijpharm.2017.05.015] [PMID: 28495580]
[80]
Fan, S.; Zheng, Y.; Liu, X.; Fang, W.; Chen, X.; Liao, W.; Jing, X.; Lei, M.; Tao, E.; Ma, Q.; Zhang, X.; Guo, R.; Liu, J. Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer’s disease. Drug Deliv., 2018, 25(1), 1091-1102.
[http://dx.doi.org/10.1080/10717544.2018.1461955] [PMID: 30107760]
[81]
Huo, X.; Zhang, Y.; Jin, X.; Li, Y.; Zhang, L. A novel synthesis of selenium nanoparticles encapsulated PLGA nanospheres with curcumin molecules for the inhibition of amyloid β aggregation in Alzheimer’s disease. J. Photochem. Photobiol. B, 2019, 190, 98-102.
[http://dx.doi.org/10.1016/j.jphotobiol.2018.11.008] [PMID: 30504054]
[82]
Gao, C.; Chu, X.; Gong, W.; Zheng, J.; Xie, X.; Wang, Y.; Yang, M.; Li, Z.; Gao, C.; Yang, Y. Neuron tau-targeting biomimetic nanoparticles for curcumin delivery to delay progression of Alzheimer’s disease. J. Nanobiotechnology, 2020, 18(1), 71.
[http://dx.doi.org/10.1186/s12951-020-00626-1] [PMID: 32404183]
[83]
Gao, C.; Wang, Y.; Sun, J.; Han, Y.; Gong, W.; Li, Y.; Feng, Y.; Wang, H.; Yang, M.; Li, Z.; Yang, Y.; Gao, C. Neuronal mitochondria-targeted delivery of curcumin by biomimetic engineered nanosystems in Alzheimer’s disease mice. Acta Biomater., 2020, 108, 285-299.
[http://dx.doi.org/10.1016/j.actbio.2020.03.029] [PMID: 32251785]
[84]
Sintov, A.C. AmyloLipid Nanovesicles: A self-assembled lipid-modified starch hybrid system constructed for direct nose-to-brain delivery of curcumin. Int. J. Pharm., 2020, 588, 119725.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119725] [PMID: 32763387]
[85]
Zhang, L.; Yang, S.; Wong, L.R.; Xie, H.; Ho, P.C. In vitro and in vivo comparison of curcumin-encapsulated chitosan-coated poly(lactic-co-glycolic acid) nanoparticles and curcumin/hydroxypropyl-β-cyclodextrin inclusion complexes administered intranasally as therapeutic strategies for Alzheimer’s disease. Mol. Pharm., 2020, 17(11), 4256-4269.
[http://dx.doi.org/10.1021/acs.molpharmaceut.0c00675] [PMID: 33084343]
[86]
Wong, S.K.; Chin, K.Y.; Ima-Nirwana, S. Quercetin as an agent for protecting the bone: A review of the current evidence. Int. J. Mol. Sci., 2020, 21(17), 6448.
[http://dx.doi.org/10.3390/ijms21176448] [PMID: 32899435]
[87]
Ali, A.H.; Sudi, S.; Shi-Jing, N.; Hassan, W.R.M.; Basir, R.; Agustar, H.K.; Embi, N.; Sidek, H.M.; Latip, J. Dual anti-malarial and GSK3β-mediated cytokine-modulating activities of quercetin are requisite of its potential as a plant-derived therapeutic in malaria. Pharmaceuticals (Basel), 2021, 14(3), 248.
[http://dx.doi.org/10.3390/ph14030248] [PMID: 33803419]
[88]
Zaplatic, E.; Bule, M.; Shah, S.Z.A.; Uddin, M.S.; Niaz, K. Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci., 2019, 224, 109-119.
[http://dx.doi.org/10.1016/j.lfs.2019.03.055] [PMID: 30914316]
[89]
Han, Q.; Wang, X.; Cai, S.; Liu, X.; Zhang, Y.; Yang, L.; Wang, C.; Yang, R. Quercetin nanoparticles with enhanced bioavailability as multifunctional agents toward amyloid induced neurotoxicity. J. Mater. Chem. B Mater. Biol. Med., 2018, 6(9), 1387-1393.
[http://dx.doi.org/10.1039/C7TB03053C] [PMID: 32254423]
[90]
Pinheiro, R.G.R.; Granja, A.; Loureiro, J.A.; Pereira, M.C.; Pinheiro, M.; Neves, A.R.; Reis, S. Quercetin lipid nanoparticles functionalized with transferrin for Alzheimer’s disease. Eur. J. Pharm. Sci., 2020, 148, 105314.
[http://dx.doi.org/10.1016/j.ejps.2020.105314] [PMID: 32200044]
[91]
Pinheiro, R.G.R.; Granja, A.; Loureiro, J.A.; Pereira, M.C.; Pinheiro, M.; Neves, A.R.; Reis, S. RVG29-functionalized lipid nanoparticles for quercetin brain delivery and Alzheimer’s disease. Pharm. Res., 2020, 37(7), 139.
[http://dx.doi.org/10.1007/s11095-020-02865-1] [PMID: 32661727]
[92]
Moreno, L.C.G.E.I.; Puerta, E.; Suárez-Santiago, J.E.; Santos-Magalhães, N.S.; Ramirez, M.J.; Irache, J.M. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int. J. Pharm., 2017, 517(1-2), 50-57.
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.061] [PMID: 27915007]
[93]
Enteshari Najafabadi, R.; Kazemipour, N.; Esmaeili, A.; Beheshti, S.; Nazifi, S. Using superparamagnetic iron oxide nanoparticles to enhance bioavailability of quercetin in the intact rat brain. BMC Pharmacol. Toxicol., 2018, 19(1), 59.
[http://dx.doi.org/10.1186/s40360-018-0249-7] [PMID: 30253803]
[94]
Qi, Y.; Guo, L.; Jiang, Y.; Shi, Y.; Sui, H.; Zhao, L. Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles. Drug Deliv., 2020, 27(1), 745-755.
[http://dx.doi.org/10.1080/10717544.2020.1762262] [PMID: 32397764]
[95]
Liu, Y.; Zhou, H.; Yin, T.; Gong, Y.; Yuan, G.; Chen, L.; Liu, J. Quercetin-modified gold-palladium nanoparticles as a potential autophagy inducer for the treatment of Alzheimer’s disease. J. Colloid Interface Sci., 2019, 552, 388-400.
[http://dx.doi.org/10.1016/j.jcis.2019.05.066] [PMID: 31151017]
[96]
Halevas, E.; Mavroidi, B.; Nday, C.M.; Tang, J.; Smith, G.C.; Boukos, N.; Litsardakis, G.; Pelecanou, M.; Salifoglou, A. Modified magnetic core-shell mesoporous silica nano-formulations with encapsulated quercetin exhibit anti-amyloid and antioxidant activity. J. Inorg. Biochem., 2020, 213, 111271.
[http://dx.doi.org/10.1016/j.jinorgbio.2020.111271] [PMID: 33069945]
[97]
Qi, Y.; Yi, P.; He, T. Quercetin-loaded selenium nanoparticles inhibit amyloid-β aggregation and exhibit antioxidant activity. Colloids Surf. A Physicochem. Eng. Asp., 2020, 602, 125058.
[http://dx.doi.org/10.1016/j.colsurfa.2020.125058]
[98]
Liu, Y.; Gong, Y.; Xie, W.; Huang, A.; Yuan, X.; Zhou, H.; Zhu, X.; Chen, X.; Liu, J.; Liu, J.; Qin, X. Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer’s disease. Nanoscale, 2020, 12(11), 6498-6511.
[http://dx.doi.org/10.1039/C9NR09713A] [PMID: 32154811]
[99]
Rifaai, R.A.; Mokhemer, S.A.; Saber, E.A.; El-Aleem, S.A.A.; El-Tahawy, N.F.G. Neuroprotective effect of quercetin nanoparticles: A possible prophylactic and therapeutic role in alzheimer’s disease. J. Chem. Neuroanat., 2020, 107, 101795.
[http://dx.doi.org/10.1016/j.jchemneu.2020.101795] [PMID: 32464160]
[100]
Amanzadeh, E.; Esmaeili, A.; Abadi, R.E.N.; Kazemipour, N.; Pahlevanneshan, Z.; Beheshti, S. Quercetin conjugated with superparamagnetic iron oxide nanoparticles improves learning and memory better than free quercetin via interacting with proteins involved in LTP. Sci. Rep., 2019, 9(1), 6876.
[http://dx.doi.org/10.1038/s41598-019-43345-w] [PMID: 31053743]
[101]
Nagapan, T.S.; Ghazali, A.R.; Basri, D.F.; Lim, W.N. Oral administration of resveratrol ameliorates epidermal hyperplasia in ultraviolet B irradiated BALB/c mice. J. Appl. Pharm. Sci., 2018, 8(10), 47-52.
[http://dx.doi.org/10.7324/JAPS.2018.81007]
[102]
Ramalingam, A.; Santhanathas, T.; Shaukat Ali, S.; Zainalabidin, S. Resveratrol supplementation protects against nicotine-induced kidney injury. Int. J. Environ. Res. Public Health, 2019, 16(22), 4445.
[http://dx.doi.org/10.3390/ijerph16224445] [PMID: 31726798]
[103]
Chen, J.Y.; Zhu, Q.; Zhang, S.; OuYang, D.; Lu, J.H. Resveratrol in experimental Alzheimer’s disease models: A systematic review of preclinical studies. Pharmacol. Res., 2019, 150, 104476.
[http://dx.doi.org/10.1016/j.phrs.2019.104476] [PMID: 31605783]
[104]
Loureiro, J.A.; Andrade, S.; Duarte, A.; Neves, A.R.; Queiroz, J.F.; Nunes, C.; Sevin, E.; Fenart, L.; Gosselet, F.; Coelho, M.A.; Pereira, M.C. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules, 2017, 22(2), 277.
[http://dx.doi.org/10.3390/molecules22020277] [PMID: 28208831]
[105]
Yang, L.; Wang, W.; Chen, J.; Wang, N.; Zheng, G. A comparative study of resveratrol and resveratrol-functional selenium nanoparticles: Inhibiting amyloid β aggregation and reactive oxygen species formation properties. J. Biomed. Mater. Res. A, 2018, 106(12), 3034-3041.
[http://dx.doi.org/10.1002/jbm.a.36493] [PMID: 30295993]
[106]
Anand, A.; Arya, M.; Singh, G.; Kaithwas, G.; Saraf, S.A. Design and development of resveratrol NLCs and their role in synaptic transmission of acetylcholine in C. elegans model. Curr. Drug Ther., 2017, 12(2), 134-148.
[http://dx.doi.org/10.2174/1574885512666170529114325]
[107]
Anekonda, T.S. Resveratrol--a boon for treating Alzheimer’s disease? Brain Res. Brain Res. Rev., 2006, 52(2), 316-326.
[http://dx.doi.org/10.1016/j.brainresrev.2006.04.004] [PMID: 16766037]
[108]
Han, Y.; Chu, X.; Cui, L.; Fu, S.; Gao, C.; Li, Y.; Sun, B. Neuronal mitochondria-targeted therapy for Alzheimer’s disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems. Drug Deliv., 2020, 27(1), 502-518.
[http://dx.doi.org/10.1080/10717544.2020.1745328] [PMID: 32228100]
[109]
Rajput, A.P.; Butani, S.B. Resveratrol anchored nanostructured lipid carrier loaded in situ gel via nasal route: Formulation, optimization and in vivo characterization. J. Drug Deliv. Sci. Technol., 2019, 51, 214-223.
[http://dx.doi.org/10.1016/j.jddst.2019.01.040]
[110]
Rajput, A.; Bariya, A.; Allam, A.; Othman, S.; Butani, S.B. In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization. Drug Deliv. Transl. Res., 2018, 8(5), 1460-1470.
[http://dx.doi.org/10.1007/s13346-018-0540-6] [PMID: 29785574]
[111]
Salem, H.F.; Kharshoum, R.M.; Abou-Taleb, H.A.; Naguib, D.M. Brain targeting of resveratrol through intranasal lipid vesicles labelled with gold nanoparticles: in vivo evaluation and bioaccumulation investigation using computed tomography and histopathological examination. J. Drug Target., 2019, 27(10), 1127-1134.
[http://dx.doi.org/10.1080/1061186X.2019.1608553] [PMID: 31094230]
[112]
Bobe, G.; Zhang, Z.; Kopp, R.; Garzotto, M.; Shannon, J.; Takata, Y. Phytol and its metabolites phytanic and pristanic acids for risk of cancer: current evidence and future directions. Eur. J. Cancer Prev., 2020, 29(2), 191-200.
[http://dx.doi.org/10.1097/CEJ.0000000000000534] [PMID: 31436750]
[113]
Carvalho, A.M.S.; Heimfarth, L.; Pereira, E.W.M.; Oliveira, F.S.; Menezes, I.R.A.; Coutinho, H.D.M.; Picot, L.; Antoniolli, A.R.; Quintans, J.S.S.; Quintans-Júnior, L.J. Phytol, a chlorophyll component, produces antihyperalgesic, anti-inflammatory, and antiarthritic effects: Possible NFκB Pathway involvement and reduced levels of the proinflammatory cytokines TNF-α and IL-6. J. Nat. Prod., 2020, 83(4), 1107-1117.
[http://dx.doi.org/10.1021/acs.jnatprod.9b01116] [PMID: 32091204]
[114]
Sathya, S.; Shanmuganathan, B.; Saranya, S.; Vaidevi, S.; Ruckmani, K.; Pandima Devi, K. Phytol-loaded PLGA nanoparticle as a modulator of Alzheimer’s toxic Aβ peptide aggregation and fibrillation associated with impaired neuronal cell function. Artif. Cells Nanomed. Biotechnol., 2018, 46(8), 1719-1730.
[PMID: 29069924]
[115]
Sathya, S.; Shanmuganathan, B.; Balasubramaniam, B.; Balamurugan, K.; Devi, K.P. Phytol loaded PLGA nanoparticles regulate the expression of Alzheimer’s related genes and neuronal apoptosis against amyloid-β induced toxicity in Neuro-2a cells and transgenic Caenorhabditis elegans. Food Chem. Toxicol., 2020, 136, 110962.
[http://dx.doi.org/10.1016/j.fct.2019.110962] [PMID: 31734340]
[116]
Sathya, S.; Manogari, B.G.; Thamaraiselvi, K.; Vaidevi, S.; Ruckmani, K.; Devi, K.P. Phytol loaded PLGA nanoparticles ameliorate scopolamine-induced cognitive dysfunction by attenuating cholinesterase activity, oxidative stress and apoptosis in Wistar rat. Nutr. Neurosci., 2020, 1-17.
[http://dx.doi.org/10.1080/1028415X.2020.1764290] [PMID: 32406811]
[117]
Khalil, P.; Masood, S.; Rehman, A.; Khalil, F.; Nawaf, J. Preventive role of thymoquinone against certain chronic health issues: A review. Int J Food Nutr Sci, 2020, 5(4), 151-158.
[118]
Sallehuddin, N.; Nordin, A.; Bt Hj Idrus, R.; Fauzi, M.B. Nigella sativa and Its active compound, thymoquinone, accelerate wound healing in an in vivo animal model: A comprehensive review. Int. J. Environ. Res. Public Health, 2020, 17(11), 4160.
[http://dx.doi.org/10.3390/ijerph17114160] [PMID: 32545210]
[119]
Cascella, M.; Bimonte, S.; Barbieri, A.; Del Vecchio, V.; Muzio, M.R.; Vitale, A.; Benincasa, G.; Ferriello, A.B.; Azzariti, A.; Arra, C.; Cuomo, A. Dissecting the potential roles of Nigella sativa and its constituent thymoquinone on the prevention and on the progression of Alzheimer’s disease. Front. Aging Neurosci., 2018, 10, 16.
[http://dx.doi.org/10.3389/fnagi.2018.00016] [PMID: 29479315]
[120]
Fahmy, H.M.; Fathy, M.M.; Abd-Elbadia, R.A.; Elshemey, W.M. Targeting of Thymoquinone-loaded mesoporous silica nanoparticles to different brain areas: In vivo study. Life Sci., 2019, 222, 94-102.
[http://dx.doi.org/10.1016/j.lfs.2019.02.058] [PMID: 30826496]
[121]
Yusuf, M.; Khan, M.; Alrobaian, M.M. Brain targeted Polysorbate-80 coated PLGA thymoquinone nanoparticles for the treatment of Alzheimer’s disease, with biomechanistic insights. J. Drug Deliv. Sci. Technol., 2021, 61, 102214.
[http://dx.doi.org/10.1016/j.jddst.2020.102214]
[122]
Ismail, N.; Ismail, M.; Azmi, N.H.; Bakar, M.F.A.; Yida, Z.; Abdullah, M.A.; Basri, H. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomed. Pharmacother., 2017, 95, 780-788.
[http://dx.doi.org/10.1016/j.biopha.2017.08.074] [PMID: 28892789]
[123]
Hou, W.; Wang, Y.; Zheng, P.; Cui, R. Effects of ginseng on neurological disorders. Front. Cell. Neurosci., 2020, 14, 55.
[http://dx.doi.org/10.3389/fncel.2020.00055] [PMID: 32265659]
[124]
Shin, S.J.; Jeon, S.G.; Kim, J.I.; Jeong, Y.O.; Kim, S.; Park, Y.H.; Lee, S.K.; Park, H.H.; Hong, S.B.; Oh, S.; Hwang, J.Y.; Kim, H.S.; Park, H.; Nam, Y.; Lee, Y.Y.; Kim, J.J.; Park, S.H.; Kim, J.S.; Moon, M. Red ginseng attenuates Aβ-induced mitochondrial dysfunction and Aβ-mediated pathology in an animal model of Alzheimer’s disease. Int. J. Mol. Sci., 2019, 20(12), 3030.
[http://dx.doi.org/10.3390/ijms20123030] [PMID: 31234321]
[125]
Wang, Y.; Li, Y.; Yang, W.; Gao, S.; Lin, J.; Wang, T.; Zhou, K.; Hu, H. Ginsenoside Rb1 inhibit apoptosis in rat model of Alzheimer’s disease induced by Aβ1-40. Am. J. Transl. Res., 2018, 10(3), 796-805.
[PMID: 29636869]
[126]
Zhang, Y.; Yang, X.; Wang, S.; Song, S. Ginsenoside Rg3 prevents cognitive impairment by improving mitochondrial dysfunction in the rat model of Alzheimer’s disease. J. Agric. Food Chem., 2019, 67(36), 10048-10058.
[http://dx.doi.org/10.1021/acs.jafc.9b03793] [PMID: 31422666]
[127]
Aalinkeel, R.; Kutscher, H.L.; Singh, A.; Cwiklinski, K.; Khechen, N.; Schwartz, S.A.; Prasad, P.N.; Mahajan, S.D. Neuroprotective effects of a biodegradable poly(lactic-co-glycolic acid)-ginsenoside Rg3 nanoformulation: a potential nanotherapy for Alzheimer’s disease? J. Drug Target., 2018, 26(2), 182-193.
[http://dx.doi.org/10.1080/1061186X.2017.1354002] [PMID: 28697660]
[128]
Tsai, S.J. Huperzine-A, a versatile herb, for the treatment of Alzheimer’s disease. J. Chin. Med. Assoc., 2019, 82(10), 750-751.
[http://dx.doi.org/10.1097/JCMA.0000000000000151] [PMID: 31305343]
[129]
Gul, A.; Bakht, J.; Mehmood, F. Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer’s disease. J. Chin. Med. Assoc., 2019, 82(1), 40-43.
[http://dx.doi.org/10.1016/j.jcma.2018.07.004] [PMID: 30839402]
[130]
Sheng, J.; Han, L.; Qin, J.; Ru, G.; Li, R.; Wu, L.; Cui, D.; Yang, P.; He, Y.; Wang, J. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl. Mater. Interfaces, 2015, 7(28), 15430-15441.
[http://dx.doi.org/10.1021/acsami.5b03555] [PMID: 26111015]
[131]
Meng, Q.; Wang, A.; Hua, H.; Jiang, Y.; Wang, Y.; Mu, H.; Wu, Z.; Sun, K. Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease. Int. J. Nanomedicine, 2018, 13, 705-718.
[http://dx.doi.org/10.2147/IJN.S151474] [PMID: 29440896]
[132]
Zaid, O.I.; Abd Majid, R.; Sabariah, M.N.; Hasidah, M.S.; Al-Zihiry, K.; Yam, M.F.; Basir, R. Andrographolide effect on both Plasmodium falciparum infected and non infected RBCs membranes. Asian Pac. J. Trop. Med., 2015, 8(7), 507-512.
[http://dx.doi.org/10.1016/j.apjtm.2015.06.007] [PMID: 26276279]
[133]
Bilia, A.R.; Nardiello, P.; Piazzini, V.; Leri, M.; Bergonzi, M.C.; Bucciantini, M.; Casamenti, F. Successful Brain delivery of andrographolide loaded in human albumin nanoparticles to TgCRND8 mice, an Alzheimer’s disease mouse model. Front. Pharmacol., 2019, 10, 910.
[http://dx.doi.org/10.3389/fphar.2019.00910] [PMID: 31507412]
[134]
Khan, A.; Ikram, M.; Hahm, J.R.; Kim, M.O. Antioxidant and anti-inflammatory effects of citrus flavonoid hesperetin: Special focus on neurological disorders. Antioxidants, 2020, 9(7), 609.
[http://dx.doi.org/10.3390/antiox9070609] [PMID: 32664395]
[135]
Muhammad, T.; Ikram, M.; Ullah, R.; Rehman, S.U.; Kim, M.O. Hesperetin, a citrus flavonoid, attenuates LPS-induced neuroinflammation, apoptosis and memory impairments by modulating TLR4/NF-κB signaling. Nutrients, 2019, 11(3), 648.
[http://dx.doi.org/10.3390/nu11030648] [PMID: 30884890]
[136]
Hajizadeh Moghaddam, A.; Ahmadnia, H.; Jelodar, S.K.; Ranjbar, M. Hesperetin nanoparticles attenuate anxiogenic-like behavior and cerebral oxidative stress through the upregulation of antioxidant enzyme expression in experimental dementia of Alzheimer’s type. Neurol. Res., 2020, 42(6), 477-486.
[http://dx.doi.org/10.1080/01616412.2020.1747716] [PMID: 32252616]
[137]
Kheradmand, E.; Hajizadeh Moghaddam, A.; Zare, M. Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer’s disease. Biomed. Pharmacother., 2018, 97, 1096-1101.
[http://dx.doi.org/10.1016/j.biopha.2017.11.047] [PMID: 29136946]
[138]
Babylon, L.; Grewal, R.; Stahr, P.L.; Eckert, R.W.; Keck, C.M.; Eckert, G.P. Hesperetin nanocrystals improve mitochondrial function in a cell model of early Alzheimer disease. Antioxidants, 2021, 10(7), 1003.
[http://dx.doi.org/10.3390/antiox10071003] [PMID: 34201544]
[139]
Zaidun, N.H.; Thent, Z.C.; Latiff, A.A. Combating oxidative stress disorders with citrus flavonoid: Naringenin. Life Sci., 2018, 208, 111-122.
[http://dx.doi.org/10.1016/j.lfs.2018.07.017] [PMID: 30021118]
[140]
Ahsan, A.U.; Sharma, V.L.; Wani, A.; Chopra, M. Naringenin upregulates AMPK-mediated autophagy to rescue neuronal cells from β-amyloid(1-42) evoked neurotoxicity. Mol. Neurobiol., 2020, 57(8), 3589-3602.
[http://dx.doi.org/10.1007/s12035-020-01969-4] [PMID: 32542594]
[141]
Khajevand-Khazaei, M.R.; Ziaee, P.; Motevalizadeh, S.A.; Rohani, M.; Afshin-Majd, S.; Baluchnejadmojarad, T.; Roghani, M. Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat. Eur. J. Pharmacol., 2018, 826, 114-122.
[http://dx.doi.org/10.1016/j.ejphar.2018.03.001] [PMID: 29518393]
[142]
Md, S.; Gan, S.Y.; Haw, Y.H.; Ho, C.L.; Wong, S.; Choudhury, H. In vitro neuroprotective effects of naringenin nanoemulsion against β-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. Int J Biol Macromol., 2018, 118(Pt A), 1211-1219.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.06.190] [PMID: 30001606]
[143]
Benelli, G. Plant-borne compounds and nanoparticles: challenges for medicine, parasitology and entomology. Environ. Sci. Pollut. Res. Int., 2018, 25(11), 10149-10150.
[http://dx.doi.org/10.1007/s11356-017-9960-y] [PMID: 29644597]
[144]
Dowlath, M.J.H.; Musthafa, S.A.; Mohamed, K.S.B.; Varjani, S.; Karuppannan, S.K.; Ramanujam, G.M.; Arunachalam, A.M.; Arunachalam, K.D.; Chandrasekaran, M.; Chang, S.W.; Chung, W.J.; Ravindran, B. Comparison of characteristics and biocompatibility of green synthesized iron oxide nanoparticles with chemical synthesized nanoparticles. Environ. Res., 2021, 201, 111585.
[http://dx.doi.org/10.1016/j.envres.2021.111585] [PMID: 34181925]
[145]
Youssif, K.A.; Haggag, E.G.; Elshamy, A.M.; Rabeh, M.A.; Gabr, N.M.; Seleem, A.; Salem, M.A.; Hussein, A.S.; Krischke, M.; Mueller, M.J.; Abdelmohsen, U.R. Anti-Alzheimer potential, metabolomic profiling and molecular docking of green synthesized silver nanoparticles of Lampranthus coccineus and Malephora lutea aqueous extracts. PLoS One, 2019, 14(11), e0223781.
[http://dx.doi.org/10.1371/journal.pone.0223781] [PMID: 31693694]
[146]
Suganthy, N.; Sri Ramkumar, V.; Pugazhendhi, A.; Benelli, G.; Archunan, G. Biogenic synthesis of gold nanoparticles from Terminalia arjuna bark extract: assessment of safety aspects and neuroprotective potential via antioxidant, anticholinesterase, and antiamyloidogenic effects. Environ. Sci. Pollut. Res. Int., 2018, 25(11), 10418-10433.
[http://dx.doi.org/10.1007/s11356-017-9789-4] [PMID: 28762049]
[147]
Rajakumar, G.; Gomathi, T.; Thiruvengadam, M.; Devi Rajeswari, V.; Kalpana, V.N.; Chung, I.M. Evaluation of anti-cholinesterase, antibacterial and cytotoxic activities of green synthesized silver nanoparticles using from Millettia pinnata flower extract. Microb. Pathog., 2017, 103, 123-128.
[http://dx.doi.org/10.1016/j.micpath.2016.12.019] [PMID: 28025099]
[148]
Faisal, S.; Khan, M.A.; Jan, H.; Shah, S.A.; Abdullah, ; Shah, S.; Rizwan, M.; Ullah, W.; Akbar, M.T.; Redaina, Edible mushroom (Flammulina velutipes) as biosource for silver nanoparticles: from synthesis to diverse biomedical and environmental applications. Nanotechnology, 2021, 32(6), 065101.
[http://dx.doi.org/10.1088/1361-6528/abc2eb] [PMID: 33119546]
[149]
Popli, D.; Anil, V.; Subramanyam, A.B. Endophyte fungi, Cladosporium species-mediated synthesis of silver nanoparticles possessing in vitro antioxidant, anti-diabetic and anti-Alzheimer activity. Artif Cells Nanomed Biotechnol., 2018, 46(sup1), 676-683.
[http://dx.doi.org/10.1080/21691401.2018.1434188] [PMID: 29400565]
[150]
Khalil, A.T.; Ayaz, M.; Ovais, M. In vitro cholinesterase enzymes inhibitory potential and in silico molecular docking studies of biogenic metal oxides nanoparticles. Inorg Nano-Met Chem, 2018, 48(9), 441-448.
[http://dx.doi.org/10.1080/24701556.2019.1569686]
[151]
El-Hawwary, S.S.; Abd Almaksoud, H.M.; Saber, F.R. Green-synthesized zinc oxide nanoparticles, anti-Alzheimer potential and the metabolic profiling of Sabal blackburniana grown in Egypt supported by molecular modelling. RSC Advances, 2021, 11(29), 18009-18025.
[http://dx.doi.org/10.1039/D1RA01725J]
[152]
Zhang, X.; Li, Y.; Hu, Y. Green synthesis of silver nanoparticles and their preventive effect in deficits in recognition and spatial memory in sporadic Alzheimer’s rat model. Colloids Surf. A Physicochem. Eng. Asp., 2020, 605, 125288.
[http://dx.doi.org/10.1016/j.colsurfa.2020.125288]
[153]
Tak, K.; Sharma, R.; Dave, V.; Jain, S.; Sharma, S. Clitoria ternatea mediated synthesis of graphene quantum dots for the treatment of Alzheimer’s disease. ACS Chem. Neurosci., 2020, 11(22), 3741-3748.
[http://dx.doi.org/10.1021/acschemneuro.0c00273] [PMID: 33119989]
[154]
Song, Y.; Wang, X.; Wang, X.; Wang, J.; Hao, Q.; Hao, J.; Hou, X. Osthole-loaded nanoemulsion enhances brain target in the treatment of Alzheimer’s disease via intranasal administration. Oxid. Med. Cell. Longev., 2021, 2021, 8844455.
[http://dx.doi.org/10.1155/2021/8844455] [PMID: 33564364]
[155]
Gutierrez, M.E.Z.; Savall, A.S.P.; da Luz Abreu, E.; Nakama, K.A.; Dos Santos, R.B.; Guedes, M.C.M.; Ávila, D.S.; Luchese, C.; Haas, S.E.; Quines, C.B.; Pinton, S. Co-nanoencapsulated meloxicam and curcumin improves cognitive impairment induced by amyloid-beta through modulation of cyclooxygenase-2 in mice. Neural Regen. Res., 2021, 16(4), 783-789.
[http://dx.doi.org/10.4103/1673-5374.295339] [PMID: 33063743]
[156]
Jia, L.; Nie, X.Q.; Ji, H.M.; Yuan, Z.X.; Li, R.S. Multiple-coated PLGA nanoparticles loading triptolide attenuate injury of a cellular model of Alzheimer’s disease. BioMed Res. Int., 2021, 2021, 8825640.
[http://dx.doi.org/10.1155/2021/8825640] [PMID: 33708996]
[157]
Songjiang, Z.; Lixiang, W. Amyloid-beta associated with chitosan nano-carrier has favorable immunogenicity and permeates the BBB. AAPS PharmSciTech, 2009, 10(3), 900-905.
[http://dx.doi.org/10.1208/s12249-009-9279-1] [PMID: 19609682]
[158]
Sun, D.; Li, N.; Zhang, W.; Zhao, Z.; Mou, Z.; Huang, D.; Liu, J.; Wang, W. Design of PLGA-functionalized quercetin nanoparticles for potential use in Alzheimer’s disease. Colloids Surf. B Biointerfaces, 2016, 148, 116-129.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.052] [PMID: 27591943]
[159]
Talebpour, F.; Ghahghaei, A. Effect of green synthesis of gold nanoparticles (AuNPs) from Hibiscus sabdariffa on the aggregation of α-lactalbumin. Int. J. Pept. Res. Ther., 2020, 26(4), 2297-2306.
[http://dx.doi.org/10.1007/s10989-020-10023-9]
[160]
Dehvari, M.; Ghahghaei, A. The effect of green synthesis silver nanoparticles (AgNPs) from Pulicaria undulata on the amyloid formation in α-lactalbumin and the chaperon action of α-casein. Int. J. Biol. Macromol., 2018, 108, 1128-1139.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.12.040] [PMID: 29225181]
[161]
Amanzadeh Jajin, E.; Esmaeili, A.; Rahgozar, S.; Noorbakhshnia, M. Quercetin-conjugated superparamagnetic iron oxide nanoparticles protect AlCl3-induced neurotoxicity in a rat model of Alzheimer’s disease via antioxidant genes, APP Gene, and miRNA-101. Front. Neurosci., 2021, 14, 598617.
[http://dx.doi.org/10.3389/fnins.2020.598617] [PMID: 33716639]
[162]
Lin, Y.; Liang, X.; Yao, Y.; Xiao, H.; Shi, Y.; Yang, J. Osthole attenuates APP-induced Alzheimer’s disease through up-regulating miRNA-101a-3p. Life Sci., 2019, 225, 117-131.
[http://dx.doi.org/10.1016/j.lfs.2019.04.004] [PMID: 30951743]
[163]
Amin, F.U.; Shah, S.A.; Badshah, H.; Khan, M.; Kim, M.O. Anthocyanins encapsulated by PLGA@PEG nanoparticles potentially improved its free radical scavenging capabilities via p38/JNK pathway against Aβ1-42-induced oxidative stress. J. Nanobiotechnology, 2017, 15(1), 12.
[http://dx.doi.org/10.1186/s12951-016-0227-4] [PMID: 28173812]
[164]
Campanari, M.L.; Navarrete, F.; Ginsberg, S.D.; Manzanares, J.; Sáez-Valero, J.; García-Ayllón, M.S. Increased expression of readthrough acetylcholinesterase variants in the brains of Alzheimer’s disease patients. J. Alzheimers Dis., 2016, 53(3), 831-841.
[http://dx.doi.org/10.3233/JAD-160220] [PMID: 27258420]
[165]
Kakkar, V.; Kaur, I.P. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem. Toxicol., 2011, 49(11), 2906-2913.
[http://dx.doi.org/10.1016/j.fct.2011.08.006] [PMID: 21889563]
[166]
Jaiswal, M.; Kumar, A.; Sharma, S. Nanoemulsions loaded Carbopol® 934 based gel for intranasal delivery of neuroprotective Centella asiatica extract: in-vitro and ex-vivo permeation study. Int. J. Pharm. Investig., 2016, 46(1), 79-89.
[http://dx.doi.org/10.1007/s40005-016-0228-1]
[167]
Ismail, N.; Ismail, M.; Azmi, N.H.; Bakar, M.F.A.; Yida, Z.; Stanslas, J.; Sani, D.; Basri, H.; Abdullah, M.A. Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats. Chem. Biol. Interact., 2017, 275, 61-73.
[http://dx.doi.org/10.1016/j.cbi.2017.07.014] [PMID: 28734741]
[168]
Lammari, N.; Demautis, T.; Louaer, O.; Meniai, A.H.; Casabianca, H.; Bensouici, C.; Devouassoux, G.; Fessi, H.; Bentaher, A.; Elaissari, A. Nanocapsules containing Saussurea lappa essential oil: Formulation, characterization, antidiabetic, anti-cholinesterase and anti-inflammatory potentials. Int. J. Pharm., 2021, 593, 120138.
[http://dx.doi.org/10.1016/j.ijpharm.2020.120138] [PMID: 33278497]
[169]
Morris, R.; Armbruster, K.; Silva, J.; Widell, D.J.; Cheng, F. The association between the usage of non-steroidal anti-inflammatory drugs and cognitive status: analysis of longitudinal and cross-sectional studies from the Global Alzheimer’s Association Interactive Network and Transcriptomic Data. Brain Sci., 2020, 10(12), 12.
[http://dx.doi.org/10.3390/brainsci10120961] [PMID: 33321871]
[170]
Zhang, L.; Yang, S.; Huang, L.; Ho, P.C. Poly (ethylene glycol)-block-poly (D, L-lactide) (PEG-PLA) micelles for brain delivery of baicalein through nasal route for potential treatment of neurodegenerative diseases due to oxidative stress and inflammation: An in vitro and in vivo study. Int. J. Pharm., 2020, 591, 119981.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119981] [PMID: 33069896]
[171]
Xu, P.; Wang, H.; Hu, H.; Ye, Y.; Dong, Y.; Li, S.; Mei, D.; Guo, Z.; Wang, D.; Sun, Y.; Yu, T.; Qiao, J.; Zhang, Q. cRGDfK-grafted small-size quercetin micelles for enhancing therapy efficacy of active ingredient from the Chinese medicinal herb. Int. J. Nanomedicine, 2019, 14, 9173-9184.
[http://dx.doi.org/10.2147/IJN.S219578] [PMID: 31819425]
[172]
Itaya, M.; Miyazawa, T.; Zingg, J.M.; Eitsuka, T.; Azzi, A.; Meydani, M.; Miyazawa, T.; Nakagawa, K. The differential cellular uptake of curcuminoids in vitro depends dominantly on albumin interaction. Phytomedicine, 2019, 59, 152902.
[http://dx.doi.org/10.1016/j.phymed.2019.152902] [PMID: 30981184]
[173]
Wu, W.H.; Sun, X.; Yu, Y.P.; Hu, J.; Zhao, L.; Liu, Q.; Zhao, Y.F.; Li, Y.M. TiO2 nanoparticles promote β-amyloid fibrillation in vitro. Biochem. Biophys. Res. Commun., 2008, 373(2), 315-318.
[http://dx.doi.org/10.1016/j.bbrc.2008.06.035] [PMID: 18571499]
[174]
Mahmoudi, M.; Quinlan-Pluck, F.; Monopoli, M.P.; Sheibani, S.; Vali, H.; Dawson, K.A.; Lynch, I. Influence of the physiochemical properties of superparamagnetic iron oxide nanoparticles on amyloid β protein fibrillation in solution. ACS Chem. Neurosci., 2013, 4(3), 475-485.
[http://dx.doi.org/10.1021/cn300196n] [PMID: 23509983]
[175]
Barua, S.; Mitragotri, S. Challenges associated with penetration of nanoparticles across cell and tissue barriers: A review of current status and future prospects. Nano Today, 2014, 9(2), 223-243.
[http://dx.doi.org/10.1016/j.nantod.2014.04.008] [PMID: 25132862]
[176]
Feng, X.; Chen, A.; Zhang, Y.; Wang, J.; Shao, L.; Wei, L. Central nervous system toxicity of metallic nanoparticles. Int. J. Nanomedicine, 2015, 10, 4321-4340.
[PMID: 26170667]
[177]
Ceña, V.; Játiva, P. Nanoparticle crossing of blood-brain barrier: a road to new therapeutic approaches to central nervous system diseases. Nanomedicine (Lond.), 2018, 13(13), 1513-1516.
[http://dx.doi.org/10.2217/nnm-2018-0139] [PMID: 29998779]
[178]
Khan, N.H.; Mir, M.; Ngowi, E.E.; Zafar, U.; Khakwani, M.M.A.K.; Khattak, S.; Zhai, Y.K.; Jiang, E.S.; Zheng, M.; Duan, S.F.; Wei, J.S.; Wu, D.D.; Ji, X.Y. Nanomedicine: A promising way to manage Alzheimer’s disease. Front. Bioeng. Biotechnol., 2021, 9, 630055.
[http://dx.doi.org/10.3389/fbioe.2021.630055] [PMID: 33996777]
[179]
Karthivashan, G.; Ganesan, P.; Park, S.Y.; Kim, J.S.; Choi, D.K. Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease. Drug Deliv., 2018, 25(1), 307-320.
[http://dx.doi.org/10.1080/10717544.2018.1428243] [PMID: 29350055]

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      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=26) and sj.journal_id!=26 group by `j`.`nid`) as `aggregate_table`
      1.13msalphaeurekaselec_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=26) and sj.journal_id!=26 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      930μsalphaeurekaselec_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=26) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.47msalphaeurekaselec_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=26) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.36msalphaeurekaselec_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` = '119503'
      1.46msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 119503
      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` = '119503'
      4.18msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 119503
      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` = '119503' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.46msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 119503
      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
      240μsalphaeurekaselec_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
      460μsalphaeurekaselec_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 = 26 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      35.35msalphaeurekaselec_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 = 26 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      16.83msalphaeurekaselec_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 = 26 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      13.03msalphaeurekaselec_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` = 119503 limit 1
      290μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 119503
      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 = 119503 and content_type = 'article' order by status desc limit 1
      330μsalphaeurekaselec_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` = 199139 limit 1
      260μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 199139
      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
      260μsalphaeurekaselec_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` = 'CN' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      380μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CN
      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 = '119503' 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) )
      570μsalphaeurekaselec_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 = '11562' 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) )
      420μsalphaeurekaselec_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 = '3234' 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) )
      380μsalphaeurekaselec_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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3234) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3234) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3234)
      6.48msalphaeurekaselec_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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11562) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11562) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11562)
      790μsalphaeurekaselec_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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 119503) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 119503) 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 <= 58953283 and j.to_ip >=58953283 )) and ((j.from_date <= 1739988178 and j.to_date >= 1739988178 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 119503)
      810μsalphaeurekaselec_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` < '1498' and is_uploaded = 1 and issue_id = 11562 order by cast(first_page as SIGNED) desc limit 1
      680μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1498
      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` > '1518' and is_uploaded = 1 and issue_id = 11562 order by cast(first_page as SIGNED) asc limit 1
      540μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1518
      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'
      180μsalphaeurekaselec_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
      200μsalphaeurekaselec_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` = 119503 limit 1
      2.43msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 119503
      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` = 26 and `b`.`banner_from_date` <= 1739988178 and `b`.`banner_to_date` >= 1739988178 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.14msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1739988178
      • 4: 1739988178
      • 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` = 26 and `b`.`banner_from_date` <= 1739988178 and `b`.`banner_to_date` >= 1739988178 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.15msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1739988178
      • 4: 1739988178
      • 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='380e6abf29336021270f94f4b2d58ff3'
      230μsalphaeurekaselec_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
        6vh8nPoce7K3YKUCpmiiCEpMz5og0A38CsGss73h
        uc_cart_id
        380e6abf29336021270f94f4b2d58ff3
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/119503" ]
        _flash
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        PHPDEBUGBAR_STACK_DATA
        []
        path_info
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        status_code
        200
        
        status_text
        OK
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        text/html; charset=UTF-8
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        request_request
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        0 of 0
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        request_cookies
        []
        
        response_headers
        0 of 0
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 18:02:59GET/article/119503414361