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Current Neuropharmacology

Editor-in-Chief

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

Review Article

The Therapeutic Potential of Mitochondria Transplantation Therapy in Neurodegenerative and Neurovascular Disorders

Author(s): Mohammad Moshahid Khan*, Hector G. Paez, Christopher R. Pitzer and Stephen E. Alway

Volume 21, Issue 5, 2023

Published on: 13 March, 2023

Page: [1100 - 1116] Pages: 17

DOI: 10.2174/1570159X05666220908100545

Price: $65

Abstract

Neurodegenerative and neurovascular disorders affect millions of people worldwide and account for a large and increasing health burden on the general population. Thus, there is a critical need to identify potential disease-modifying treatments that can prevent or slow the disease progression. Mitochondria are highly dynamic organelles and play an important role in energy metabolism and redox homeostasis, and mitochondrial dysfunction threatens cell homeostasis, perturbs energy production, and ultimately leads to cell death and diseases. Impaired mitochondrial function has been linked to the pathogenesis of several human neurological disorders. Given the significant contribution of mitochondrial dysfunction in neurological disorders, there has been considerable interest in developing therapies that can attenuate mitochondrial abnormalities and proffer neuroprotective effects. Unfortunately, therapies that target specific components of mitochondria or oxidative stress pathways have exhibited limited translatability. To this end, mitochondrial transplantation therapy (MTT) presents a new paradigm of therapeutic intervention, which involves the supplementation of healthy mitochondria to replace the damaged mitochondria for the treatment of neurological disorders. Prior studies demonstrated that the supplementation of healthy donor mitochondria to damaged neurons promotes neuronal viability, activity, and neurite growth and has been shown to provide benefits for neural and extra-neural diseases. In this review, we discuss the significance of mitochondria and summarize an overview of the recent advances and development of MTT in neurodegenerative and neurovascular disorders, particularly Parkinson’s disease, Alzheimer’s disease, and stroke. The significance of MTT is emerging as they meet a critical need to develop a diseasemodifying intervention for neurodegenerative and neurovascular disorders.

Keywords: Mitochondria, Mitochondrial medicine, Mitochondria transplantation therapy, Alzheimer’s disease, Parkinson’s disease, and Stroke

[1]
Cooper, J.M.; Schapira, A.H.V. Mitochondrial dysfunction in neurodegeneration. J. Bioenerg. Biomembr., 1997, 29(2), 175-183.
[http://dx.doi.org/10.1023/A:1022642114734] [PMID: 9239542]
[2]
Moreira, P.I.; Zhu, X.; Wang, X.; Lee, H.; Nunomura, A.; Petersen, R.B.; Perry, G.; Smith, M.A. Mitochondria: A therapeutic target in neurodegeneration. Biochim. Biophys. Acta Mol. Basis Dis., 2010, 1802(1), 212-220.
[http://dx.doi.org/10.1016/j.bbadis.2009.10.007] [PMID: 19853657]
[3]
Luo, Y.; Hoffer, A.; Hoffer, B.; Qi, X. Mitochondria: A therapeutic target for Parkinson’s Disease? Int. J. Mol. Sci., 2015, 16(9), 20704-20730.
[http://dx.doi.org/10.3390/ijms160920704] [PMID: 26340618]
[4]
He, Z.; Ning, N.; Zhou, Q.; Khoshnam, S.E.; Farzaneh, M. Mitochondria as a therapeutic target for ischemic stroke. Free Radic. Biol. Med., 2020, 146, 45-58.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.11.005] [PMID: 31704373]
[5]
Tait, S.W.G.; Green, D.R. Mitochondria and cell signalling. J. Cell Sci., 2012, 125(4), 807-815.
[http://dx.doi.org/10.1242/jcs.099234] [PMID: 22448037]
[6]
Osellame, L.D.; Blacker, T.S.; Duchen, M.R. Cellular and molecular mechanisms of mitochondrial function. Best Pract. Res. Clin. Endocrinol. Metab., 2012, 26(6), 711-723.
[http://dx.doi.org/10.1016/j.beem.2012.05.003] [PMID: 23168274]
[7]
Angelova, P.R.; Abramov, A.Y. Role of mitochondrial ROS in the brain: From physiology to neurodegeneration. FEBS Lett., 2018, 592(5), 692-702.
[http://dx.doi.org/10.1002/1873-3468.12964] [PMID: 29292494]
[8]
Norat, P.; Soldozy, S.; Sokolowski, J.D.; Gorick, C.M.; Kumar, J.S.; Chae, Y.; Yağmurlu, K.; Prada, F.; Walker, M.; Levitt, M.R.; Price, R.J.; Tvrdik, P.; Kalani, M.Y.S. Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation. NPJ Regen. Med., 2020, 5(1), 22.
[http://dx.doi.org/10.1038/s41536-020-00107-x] [PMID: 33298971]
[9]
Freire, M.A. Pathophysiology of neurodegeneration following traumatic brain injury. West Indian Med. J., 2012, 61(7), 751-755.
[PMID: 23620976]
[10]
Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch., 2010, 460(2), 525-542.
[http://dx.doi.org/10.1007/s00424-010-0809-1] [PMID: 20229265]
[11]
Johnson, J.; Mercado-Ayon, E.; Mercado-Ayon, Y.; Dong, Y.N.; Halawani, S.; Ngaba, L.; Lynch, D.R. Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch. Biochem. Biophys., 2021, 702, 108698.
[http://dx.doi.org/10.1016/j.abb.2020.108698] [PMID: 33259796]
[12]
Ma, Q. Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health. Neurosci. Bull., 2008, 24(4), 265-270.
[http://dx.doi.org/10.1007/s12264-008-0402-1] [PMID: 18668156]
[13]
Ma, C.L.; Ma, X.T.; Wang, J.J.; Liu, H.; Chen, Y.F.; Yang, Y. Physical exercise induces hippocampal neurogenesis and prevents cognitive decline. Behav. Brain Res., 2017, 317, 332-339.
[http://dx.doi.org/10.1016/j.bbr.2016.09.067] [PMID: 27702635]
[14]
Oliveira, R.F.; Paiva, K.M.; da Rocha, G.S.; de Moura Freire, M.A.; de Araújo, D.P.; de Oliveira, L.C.; Guzen, F.P.; de Gois Morais, P.L.A.; de Paiva Cavalcanti, J.R.L. Neurobiological effects of forced swim exercise on the rodent hippocampus: A systematic review. Acta Neurobiol. Exp. (Warsz.), 2021, 81(1), 58-68.
[http://dx.doi.org/10.21307/ane-2021-007] [PMID: 33949162]
[15]
Zuccato, C.; Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol., 2009, 5(6), 311-322.
[http://dx.doi.org/10.1038/nrneurol.2009.54] [PMID: 19498435]
[16]
Weissmiller, A.M.; Wu, C. Current advances in using neurotrophic factors to treat neurodegenerative disorders. Transl. Neurodegener., 2012, 1(1), 14.
[http://dx.doi.org/10.1186/2047-9158-1-14] [PMID: 23210531]
[17]
Cao, J.; Hou, J.; Ping, J.; Cai, D. Advances in developing novel therapeutic strategies for Alzheimer’s disease. Mol. Neurodegener., 2018, 13(1), 64.
[http://dx.doi.org/10.1186/s13024-018-0299-8] [PMID: 30541602]
[18]
Rabchevsky, A.G.; Gollihue, J.L.; Patel, S.P. Mitochondrial transplantation strategies as potential therapeutics for central nervous system trauma. Neural Regen. Res., 2018, 13(2), 194-197.
[http://dx.doi.org/10.4103/1673-5374.226382] [PMID: 29557359]
[19]
Mukherjee, A.; Becerra, C.A.D.; Chavez, M.; Delgado, J.P.; Soto, C. Mitochondrial transplant to replenish damaged mitochondria: A novel therapeutic strategy for neurodegenerative diseases? Prog. Mol. Biol. Transl. Sci., 2021, 177, 49-63.
[http://dx.doi.org/10.1016/bs.pmbts.2020.10.001] [PMID: 33453942]
[20]
Nakamura, Y.; Park, J.H.; Hayakawa, K. Therapeutic use of extracellular mitochondria in CNS injury and disease. Exp. Neurol., 2020, 324, 113114.
[http://dx.doi.org/10.1016/j.expneurol.2019.113114] [PMID: 31734316]
[21]
Chang, C.Y.; Liang, M.Z.; Chen, L. Current progress of mitochondrial transplantation that promotes neuronal regeneration. Transl. Neurodegener., 2019, 8(1), 17.
[http://dx.doi.org/10.1186/s40035-019-0158-8] [PMID: 31210929]
[22]
Espino De la Fuente-Muñoz, C.; Arias, C. The therapeutic potential of mitochondrial transplantation for the treatment of neurodegenerative disorders. Rev. Neurosci., 2021, 32(2), 203-217.
[http://dx.doi.org/10.1515/revneuro-2020-0068] [PMID: 33550783]
[23]
Shi, X.; Zhao, M.; Fu, C.; Fu, A. Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion, 2017, 34, 91-100.
[http://dx.doi.org/10.1016/j.mito.2017.02.005] [PMID: 28242362]
[24]
Nitzan, K.; Benhamron, S.; Valitsky, M.; Kesner, E.E.; Lichtenstein, M.; Ben-Zvi, A.; Ella, E.; Segalstein, Y.; Saada, A.; Lorberboum-Galski, H.; Rosenmann, H. Mitochondrial transfer ameliorates cognitive deficits, neuronal loss, and gliosis in Alzheimer’s disease mice. J. Alzheimers Dis., 2019, 72(2), 587-604.
[http://dx.doi.org/10.3233/JAD-190853] [PMID: 31640104]
[25]
Zhao, Z.; Yu, Z.; Hou, Y.; Zhang, L.; Fu, A. Improvement of cognitive and motor performance with mitotherapy in aged mice. Int. J. Biol. Sci., 2020, 16(5), 849-858.
[http://dx.doi.org/10.7150/ijbs.40886] [PMID: 32071554]
[26]
Alexander, J.F.; Seua, A.V.; Arroyo, L.D.; Ray, P.R.; Wangzhou, A.; Heiß-Lückemann, L.; Schedlowski, M.; Price, T.J.; Kavelaars, A.; Heijnen, C.J. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics, 2021, 11(7), 3109-3130.
[http://dx.doi.org/10.7150/thno.53474] [PMID: 33537077]
[27]
Chang, J.C.; Chao, Y.C.; Chang, H.S.; Wu, Y.L.; Chang, H.J.; Lin, Y.S.; Cheng, W.L.; Lin, T.T.; Liu, C.S. Intranasal delivery of mitochondria for treatment of Parkinson’s Disease model rats lesioned with 6-hydroxydopamine. Sci. Rep., 2021, 11(1), 10597.
[http://dx.doi.org/10.1038/s41598-021-90094-w] [PMID: 34011937]
[28]
Kaza, A.K.; Wamala, I.; Friehs, I.; Kuebler, J.D.; Rathod, R.H.; Berra, I.; Ericsson, M.; Yao, R.; Thedsanamoorthy, J.K.; Zurakowski, D.; Levitsky, S.; del Nido, P.J.; Cowan, D.B.; McCully, J.D. Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion. J. Thorac. Cardiovasc. Surg., 2017, 153(4), 934-943.
[http://dx.doi.org/10.1016/j.jtcvs.2016.10.077] [PMID: 27938904]
[29]
Zhang, Z.; Ma, Z.; Yan, C.; Pu, K.; Wu, M.; Bai, J.; Li, Y.; Wang, Q. Muscle-derived autologous mitochondrial transplantation: A novel strategy for treating cerebral ischemic injury. Behav. Brain Res., 2019, 356, 322-331.
[http://dx.doi.org/10.1016/j.bbr.2018.09.005] [PMID: 30213662]
[30]
Kitani, T.; Kami, D.; Matoba, S.; Gojo, S. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J. Cell. Mol. Med., 2014, 18(8), 1694-1703.
[http://dx.doi.org/10.1111/jcmm.12316] [PMID: 24912369]
[31]
Wang, Y.; Ni, J.; Gao, C.; Xie, L.; Zhai, L.; Cui, G.; Yin, X. Mitochondrial transplantation attenuates lipopolysaccharide- induced depression-like behaviors. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2019, 93, 240-249.
[http://dx.doi.org/10.1016/j.pnpbp.2019.04.010] [PMID: 31022424]
[32]
Zhang, J.; Liu, H.; Luo, S.; Lu, Z.; Chávez-Badiola, A.; Liu, Z.; Yang, M.; Merhi, Z.; Silber, S.J.; Munné, S.; Konstantinidis, M.; Wells, D.; Tang, J.J.; Huang, T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod. Biomed. Online, 2017, 34(4), 361-368.
[http://dx.doi.org/10.1016/j.rbmo.2017.01.013] [PMID: 28385334]
[33]
McCully, J.D.; Cowan, D.B.; Emani, S.M.; del Nido, P.J. Mitochondrial transplantation: From animal models to clinical use in humans. Mitochondrion, 2017, 34, 127-134.
[http://dx.doi.org/10.1016/j.mito.2017.03.004] [PMID: 28342934]
[34]
Cowan, D.B.; Yao, R.; Akurathi, V.; Snay, E.R.; Thedsanamoorthy, J.K.; Zurakowski, D.; Ericsson, M.; Friehs, I.; Wu, Y.; Levitsky, S.; del Nido, P.J.; Packard, A.B.; McCully, J.D. Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection. PLoS One, 2016, 11(8), e0160889.
[http://dx.doi.org/10.1371/journal.pone.0160889] [PMID: 27500955]
[35]
Emani, S.M.; Piekarski, B.L.; Harrild, D.; del Nido, P.J.; McCully, J.D. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg., 2017, 154(1), 286-289.
[http://dx.doi.org/10.1016/j.jtcvs.2017.02.018] [PMID: 28283239]
[36]
Valenti, D.; Vacca, R.A.; Moro, L.; Atlante, A. Mitochondria can cross cell boundaries: An overview of the biological relevance, pathophysiological implications and therapeutic perspectives of intercellular mitochondrial transfer. Int. J. Mol. Sci., 2021, 22(15), 8312.
[http://dx.doi.org/10.3390/ijms22158312] [PMID: 34361078]
[37]
Chou, S.H.Y.; Lan, J.; Esposito, E.; Ning, M.; Balaj, L.; Ji, X.; Lo, E.H.; Hayakawa, K. Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke, 2017, 48(8), 2231-2237.
[http://dx.doi.org/10.1161/STROKEAHA.117.017758] [PMID: 28663512]
[38]
Ruan, L.; Zhou, C.; Jin, E.; Kucharavy, A.; Zhang, Y.; Wen, Z.; Florens, L.; Li, R. Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature, 2017, 543(7645), 443-446.
[http://dx.doi.org/10.1038/nature21695] [PMID: 28241148]
[39]
Cenini, G.; Voos, W. Mitochondria as potential targets in Alzheimer disease therapy: an update. Front. Pharmacol., 2019, 10, 902.
[http://dx.doi.org/10.3389/fphar.2019.00902] [PMID: 31507410]
[40]
Aon, M.A.; Cortassa, S.; Juhaszova, M.; Sollott, S.J. Mitochondrial health, the epigenome and healthspan. Clin. Sci. (Lond.), 2016, 130(15), 1285-1305.
[http://dx.doi.org/10.1042/CS20160002] [PMID: 27358026]
[41]
Xu, S.; Zhang, X.; Liu, C.; Liu, Q.; Chai, H.; Luo, Y.; Li, S. Role of mitochondria in neurodegenerative diseases: from an epigenetic perspective. Front. Cell Dev. Biol., 2021, 9, 688789.
[http://dx.doi.org/10.3389/fcell.2021.688789] [PMID: 34513831]
[42]
Friedman, J.R.; Nunnari, J. Mitochondrial form and function. Nature, 2014, 505(7483), 335-343.
[http://dx.doi.org/10.1038/nature12985] [PMID: 24429632]
[43]
Slee, E.A.; Adrain, C.; Martin, S.J. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J. Biol. Chem., 2001, 276(10), 7320-7326.
[http://dx.doi.org/10.1074/jbc.M008363200] [PMID: 11058599]
[44]
Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The molecular machinery of regulated cell death. Cell Res., 2019, 29(5), 347-364.
[http://dx.doi.org/10.1038/s41422-019-0164-5] [PMID: 30948788]
[45]
Sheng, Z.H. Mitochondrial trafficking and anchoring in neurons: New insight and implications. J. Cell Biol., 2014, 204(7), 1087-1098.
[http://dx.doi.org/10.1083/jcb.201312123] [PMID: 24687278]
[46]
Guan, R.; Zou, W.; Dai, X.; Yu, X.; Liu, H.; Chen, Q.; Teng, W. Mitophagy, a potential therapeutic target for stroke. J. Biomed. Sci., 2018, 25(1), 87.
[http://dx.doi.org/10.1186/s12929-018-0487-4] [PMID: 30501621]
[47]
Yang, J.L.; Mukda, S.; Chen, S.D. Diverse roles of mitochondria in ischemic stroke. Redox Biol., 2018, 16, 263-275.
[http://dx.doi.org/10.1016/j.redox.2018.03.002] [PMID: 29549824]
[48]
Shen, L.; Gan, Q.; Yang, Y.; Reis, C.; Zhang, Z.; Xu, S.; Zhang, T.; Sun, C. Mitophagy in cerebral ischemia and ischemia/reperfusion injury. Front. Aging Neurosci., 2021, 13, 687246.
[http://dx.doi.org/10.3389/fnagi.2021.687246] [PMID: 34168551]
[49]
El-Hayek, Y.H.; Wiley, R.E.; Khoury, C.P.; Daya, R.P.; Ballard, C.; Evans, A.R.; Karran, M.; Molinuevo, J.L.; Norton, M.; Atri, A. Tip of the iceberg: assessing the global socioeconomic costs of Alzheimer’s disease and related dementias and strategic implications for stakeholders. J. Alzheimers Dis., 2019, 70(2), 323-341.
[http://dx.doi.org/10.3233/JAD-190426] [PMID: 31256142]
[50]
Abolhassani, N; Leon, J; Sheng, Z; Oka, S; Hamasaki, H; Iwaki, T Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain. Mech Ageing Dev., 2017, 161(Pt A), 95-104.
[http://dx.doi.org/10.1016/j.mad.2016.05.005]
[51]
Nakabeppu, Y. Molecular pathophysiology of insulin depletion, mitochondrial dysfunction, and oxidative stress in Alzheimer’s disease brain. Adv. Exp. Med. Biol., 2019, 1128, 27-44.
[http://dx.doi.org/10.1007/978-981-13-3540-2_3] [PMID: 31062324]
[52]
Moreira, P.I.; Carvalho, C.; Zhu, X.; Smith, M.A.; Perry, G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim. Biophys. Acta Mol. Basis Dis., 2010, 1802(1), 2-10.
[http://dx.doi.org/10.1016/j.bbadis.2009.10.006] [PMID: 19853658]
[53]
Manczak, M.; Kandimalla, R.; Yin, X.; Reddy, P.H. Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Hum. Mol. Genet., 2018, 27(8), 1332-1342.
[http://dx.doi.org/10.1093/hmg/ddy042] [PMID: 29408999]
[54]
Wang, W.; Zhao, F.; Ma, X.; Perry, G.; Zhu, X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol. Neurodegener., 2020, 15(1), 30.
[http://dx.doi.org/10.1186/s13024-020-00376-6] [PMID: 32471464]
[55]
Swerdlow, R.H.; Khan, S.M.A. “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med. Hypotheses, 2004, 63(1), 8-20.
[http://dx.doi.org/10.1016/j.mehy.2003.12.045] [PMID: 15193340]
[56]
Nunomura, A.; Perry, G.; Aliev, G.; Hirai, K.; Takeda, A.; Balraj, E.K.; Jones, P.K.; Ghanbari, H.; Wataya, T.; Shimohama, S.; Chiba, S.; Atwood, C.S.; Petersen, R.B.; Smith, M.A. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol., 2001, 60(8), 759-767.
[http://dx.doi.org/10.1093/jnen/60.8.759] [PMID: 11487050]
[57]
Perez Ortiz, J.M.; Swerdlow, R.H. Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br. J. Pharmacol., 2019, 176(18), 3489-3507.
[http://dx.doi.org/10.1111/bph.14585] [PMID: 30675901]
[58]
Kapogiannis, D.; Mattson, M.P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol., 2011, 10(2), 187-198.
[http://dx.doi.org/10.1016/S1474-4422(10)70277-5] [PMID: 21147038]
[59]
Croteau, E.; Castellano, C.A.; Fortier, M.; Bocti, C.; Fulop, T.; Paquet, N.; Cunnane, S.C. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp. Gerontol., 2018, 107, 18-26.
[http://dx.doi.org/10.1016/j.exger.2017.07.004] [PMID: 28709938]
[60]
Reiman, E.M.; Chen, K.; Alexander, G.E.; Caselli, R.J.; Bandy, D.; Osborne, D.; Saunders, A.M.; Hardy, J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc. Natl. Acad. Sci. USA, 2004, 101(1), 284-289.
[http://dx.doi.org/10.1073/pnas.2635903100] [PMID: 14688411]
[61]
Butterfield, D.A.; Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci., 2019, 20(3), 148-160.
[http://dx.doi.org/10.1038/s41583-019-0132-6] [PMID: 30737462]
[62]
Reddy, P.H.; Yin, X.; Manczak, M.; Kumar, S.; Pradeepkiran, J.A.; Vijayan, M.; Reddy, A.P. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum. Mol. Genet., 2018, 27(14), 2502-2516.
[http://dx.doi.org/10.1093/hmg/ddy154] [PMID: 29701781]
[63]
Calkins, M.J.; Manczak, M.; Mao, P.; Shirendeb, U.; Reddy, P.H. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum. Mol. Genet., 2011, 20(23), 4515-4529.
[http://dx.doi.org/10.1093/hmg/ddr381] [PMID: 21873260]
[64]
Misrani, A.; Tabassum, S.; Yang, L. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Front. Aging Neurosci., 2021, 13, 617588.
[http://dx.doi.org/10.3389/fnagi.2021.617588] [PMID: 33679375]
[65]
Johri, A.; Beal, M.F. Mitochondrial dysfunction in neurodegenerative diseases. J. Pharmacol. Exp. Ther., 2012, 342(3), 619-630.
[http://dx.doi.org/10.1124/jpet.112.192138] [PMID: 22700435]
[66]
Minjarez, B.; Calderón-González, K.G.; Rustarazo, M.L.V.; Herrera-Aguirre, M.E.; Labra-Barrios, M.L.; Rincon-Limas, D.E.; del Pino, M.M.S.; Mena, R.; Luna-Arias, J.P. Identification of proteins that are differentially expressed in brains with Alzheimer’s disease using iTRAQ labeling and tandem mass spectrometry. J. Proteomics, 2016, 139, 103-121.
[http://dx.doi.org/10.1016/j.jprot.2016.03.022] [PMID: 27012543]
[67]
Maurer, I.; Zierz, S.; Möller, H.J. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging, 2000, 21(3), 455-462.
[http://dx.doi.org/10.1016/S0197-4580(00)00112-3] [PMID: 10858595]
[68]
Balaban, R.S.; Nemoto, S.; Finkel, T. Mitochondria, oxidants, and aging. Cell, 2005, 120(4), 483-495.
[http://dx.doi.org/10.1016/j.cell.2005.02.001] [PMID: 15734681]
[69]
Butterfield, D.A. Perspectives on oxidative stress in Alzheimer’s disease and predictions of future research emphases. J. Alzheimers Dis., 2018, 64(s1), S469-S479.
[http://dx.doi.org/10.3233/JAD-179912] [PMID: 29504538]
[70]
Patten, D.A.; Germain, M.; Kelly, M.A.; Slack, R.S. Reactive oxygen species: stuck in the middle of neurodegeneration. J. Alzheimers Dis., 2010, 20(s2)(Suppl. 2), S357-S367.
[http://dx.doi.org/10.3233/JAD-2010-100498] [PMID: 20421690]
[71]
Jiang, T.; Sun, Q.; Chen, S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog. Neurobiol., 2016, 147, 1-19.
[http://dx.doi.org/10.1016/j.pneurobio.2016.07.005] [PMID: 27769868]
[72]
Santos, J.R.; Gois, A.M.; Mendonça, D.M.; Freire, M.A. Nutritional status, oxidative stress and dementia: the role of selenium in Alzheimer’s disease. Front. Aging Neurosci., 2014, 6, 206.
[http://dx.doi.org/10.3389/fnagi.2014.00206] [PMID: 25221506]
[73]
Reddy, P.H.; Manczak, M.; Yin, X.; Grady, M.C.; Mitchell, A.; Kandimalla, R.; Kuruva, C.S. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer’s disease. J. Investig. Med., 2016, 64(8), 1220-1234.
[http://dx.doi.org/10.1136/jim-2016-000240] [PMID: 27521081]
[74]
da Costa, I.M.; de Moura Freire, M.A.; de Paiva Cavalcanti, J.R.L.; de Araújo, D.P.; Norrara, B.; Moreira Rosa, I.M.M.; de Azevedo, E.P.; do Rego, A.C.M.; Filho, I.A.; Guzen, F.P. Supplementation with curcuma longa reverses neurotoxic and behavioral damage in models of Alzheimer’s disease: a systematic review. Curr. Neuropharmacol., 2019, 17(5), 406-421.
[http://dx.doi.org/10.2174/0929867325666180117112610] [PMID: 29338678]
[75]
Qin, W.; Haroutunian, V.; Katsel, P.; Cardozo, C.P.; Ho, L.; Buxbaum, J.D.; Pasinetti, G.M. PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch. Neurol., 2009, 66(3), 352-361.
[http://dx.doi.org/10.1001/archneurol.2008.588] [PMID: 19273754]
[76]
Sheng, B.; Wang, X.; Su, B.; Lee, H.; Casadesus, G.; Perry, G.; Zhu, X. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J. Neurochem., 2012, 120(3), 419-429.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07581.x] [PMID: 22077634]
[77]
Hirai, K.; Aliev, G.; Nunomura, A.; Fujioka, H.; Russell, R.L.; Atwood, C.S.; Johnson, A.B.; Kress, Y.; Vinters, H.V.; Tabaton, M.; Shimohama, S.; Cash, A.D.; Siedlak, S.L.; Harris, P.L.R.; Jones, P.K.; Petersen, R.B.; Perry, G.; Smith, M.A. Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci., 2001, 21(9), 3017-3023.
[http://dx.doi.org/10.1523/JNEUROSCI.21-09-03017.2001] [PMID: 11312286]
[78]
Wang, X.; Su, B.; Lee, H.; Li, X.; Perry, G.; Smith, M.A.; Zhu, X. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J. Neurosci., 2009, 29(28), 9090-9103.
[http://dx.doi.org/10.1523/JNEUROSCI.1357-09.2009] [PMID: 19605646]
[79]
Hroudová, J.; Singh, N.; Fišar, Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer’s disease. BioMed Res. Int., 2014, 2014, 1-9.
[http://dx.doi.org/10.1155/2014/175062] [PMID: 24900954]
[80]
Fang, E.F.; Hou, Y.; Palikaras, K.; Adriaanse, B.A.; Kerr, J.S.; Yang, B.; Lautrup, S.; Hasan-Olive, M.M.; Caponio, D.; Dan, X.; Rocktäschel, P.; Croteau, D.L.; Akbari, M.; Greig, N.H.; Fladby, T.; Nilsen, H.; Cader, M.Z.; Mattson, M.P.; Tavernarakis, N.; Bohr, V.A. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci., 2019, 22(3), 401-412.
[http://dx.doi.org/10.1038/s41593-018-0332-9] [PMID: 30742114]
[81]
Cai, Q.; Jeong, Y.Y. Mitophagy in Alzheimer’s disease and other age-related neurodegenerative diseases. Cells, 2020, 9(1), 150.
[http://dx.doi.org/10.3390/cells9010150] [PMID: 31936292]
[82]
Cen, X.; Chen, Y.; Xu, X.; Wu, R.; He, F.; Zhao, Q.; Sun, Q.; Yi, C.; Wu, J.; Najafov, A.; Xia, H. Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model. Nat. Commun., 2020, 11(1), 5731.
[http://dx.doi.org/10.1038/s41467-020-19547-6] [PMID: 33184293]
[83]
DeMaagd, G.; Philip, A. Parkinson’s disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P&T, 2015, 40(8), 504-532.
[PMID: 26236139]
[84]
Surmeier, D.J. Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J., 2018, 285(19), 3657-3668.
[http://dx.doi.org/10.1111/febs.14607] [PMID: 30028088]
[85]
Bose, A.; Beal, M.F. Mitochondrial dysfunction in Parkinson’s disease. J. Neurochem., 2016, 139(Suppl. 1), 216-231.
[http://dx.doi.org/10.1111/jnc.13731] [PMID: 27546335]
[86]
Ammal Kaidery, N.; Thomas, B. Current perspective of mitochondrial biology in Parkinson’s disease. Neurochem. Int., 2018, 117, 91-113.
[http://dx.doi.org/10.1016/j.neuint.2018.03.001] [PMID: 29550604]
[87]
Ryan, B.J.; Hoek, S.; Fon, E.A.; Wade-Martins, R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem. Sci., 2015, 40(4), 200-210.
[http://dx.doi.org/10.1016/j.tibs.2015.02.003] [PMID: 25757399]
[88]
Exner, N.; Lutz, A.K.; Haass, C.; Winklhofer, K.F. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J., 2012, 31(14), 3038-3062.
[http://dx.doi.org/10.1038/emboj.2012.170] [PMID: 22735187]
[89]
Hattori, N.; Tanaka, M.; Ozawa, T.; Mizuno, Y. Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in parkinson’s disease. Ann. Neurol., 1991, 30(4), 563-571.
[http://dx.doi.org/10.1002/ana.410300409] [PMID: 1665052]
[90]
Subramaniam, S.R.; Chesselet, M.F. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog. Neurobiol., 2013, 106-107, 17-32.
[http://dx.doi.org/10.1016/j.pneurobio.2013.04.004] [PMID: 23643800]
[91]
Büeler, H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp. Neurol., 2009, 218(2), 235-246.
[http://dx.doi.org/10.1016/j.expneurol.2009.03.006] [PMID: 19303005]
[92]
Santos, D.; Esteves, A.R.; Silva, D.F.; Januário, C.; Cardoso, S.M. The impact of mitochondrial fusion and fission modulation in sporadic Parkinson’s disease. Mol. Neurobiol., 2015, 52(1), 573-586.
[http://dx.doi.org/10.1007/s12035-014-8893-4] [PMID: 25218511]
[93]
Van Laar, V.S.; Arnold, B.; Howlett, E.H.; Calderon, M.J.; St Croix, C.M.; Greenamyre, J.T.; Sanders, L.H.; Berman, S.B. Evidence for compartmentalized axonal mitochondrial biogenesis: mitochondrial DNA replication increases in distal axons as an early response to Parkinson’s disease-relevant stress. J. Neurosci., 2018, 38(34), 7505-7515.
[http://dx.doi.org/10.1523/JNEUROSCI.0541-18.2018] [PMID: 30030401]
[94]
Zheng, B.; Liao, Z.; Locascio, J.J.; Lesniak, K.A.; Roderick, S.S.; Watt, M.L.; Eklund, A.C.; Zhang-James, Y.; Kim, P.D.; Hauser, M.A.; Grünblatt, E.; Moran, L.B.; Mandel, S.A.; Riederer, P.; Miller, R.M.; Federoff, H.J.; Wüllner, U.; Papapetropoulos, S.; Youdim, M.B.; Cantuti-Castelvetri, I.; Young, A.B.; Vance, J.M.; Davis, R.L.; Hedreen, J.C.; Adler, C.H.; Beach, T.G.; Graeber, M.B.; Middleton, F.A.; Rochet, J.C.; Scherzer, C.R. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci. Transl. Med., 2010, 2(52), 52ra73.
[http://dx.doi.org/10.1126/scitranslmed.3001059] [PMID: 20926834]
[95]
Kraytsberg, Y.; Kudryavtseva, E.; McKee, A.C.; Geula, C.; Kowall, N.W.; Khrapko, K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet., 2006, 38(5), 518-520.
[http://dx.doi.org/10.1038/ng1778] [PMID: 16604072]
[96]
Parker, W.D., Jr; Parks, J.K.; Swerdlow, R.H. Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res., 2008, 1189, 215-218.
[http://dx.doi.org/10.1016/j.brainres.2007.10.061] [PMID: 18061150]
[97]
Pienaar, I.S.; Elson, J.L.; Racca, C.; Nelson, G.; Turnbull, D.M.; Morris, C.M. Mitochondrial abnormality associates with type-specific neuronal loss and cell morphology changes in the pedunculopontine nucleus in Parkinson disease. Am. J. Pathol., 2013, 183(6), 1826-1840.
[http://dx.doi.org/10.1016/j.ajpath.2013.09.002] [PMID: 24099985]
[98]
Schwarz, T.L. Mitochondrial trafficking in neurons. Cold Spring Harb. Perspect. Biol., 2013, 5(6), a011304.
[http://dx.doi.org/10.1101/cshperspect.a011304] [PMID: 23732472]
[99]
Henchcliffe, C.; Beal, M.F. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat. Clin. Pract. Neurol., 2008, 4(11), 600-609.
[http://dx.doi.org/10.1038/ncpneuro0924] [PMID: 18978800]
[100]
Pickrell, A.M.; Youle, R.J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron, 2015, 85(2), 257-273.
[http://dx.doi.org/10.1016/j.neuron.2014.12.007] [PMID: 25611507]
[101]
Thomas, B; Beal, MF Parkinson's disease. Hum Mol Genet., 2007, 16(Spec No. 2), R183-94.
[102]
Trempe, J.F.; Fon, E.A. Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection. Front. Neurol., 2013, 4, 38.
[http://dx.doi.org/10.3389/fneur.2013.00038] [PMID: 23626584]
[103]
Wang, W.; Wang, X.; Fujioka, H.; Hoppel, C.; Whone, A.L.; Caldwell, M.A.; Cullen, P.J.; Liu, J.; Zhu, X. Parkinson’s disease–associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat. Med., 2016, 22(1), 54-63.
[http://dx.doi.org/10.1038/nm.3983] [PMID: 26618722]
[104]
Rocha, EM; De Miranda, B; Sanders, LH Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson's disease. Neurobiol Dis., 2018, 109(Pt B), 249-57.
[105]
Nakamura, K.; Nemani, V.M.; Azarbal, F.; Skibinski, G.; Levy, J.M.; Egami, K.; Munishkina, L.; Zhang, J.; Gardner, B.; Wakabayashi, J.; Sesaki, H.; Cheng, Y.; Finkbeiner, S.; Nussbaum, R.L.; Masliah, E.; Edwards, R.H. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J. Biol. Chem., 2011, 286(23), 20710-20726.
[http://dx.doi.org/10.1074/jbc.M110.213538] [PMID: 21489994]
[106]
Mallach, A.; Weinert, M.; Arthur, J.; Gveric, D.; Tierney, T.S.; Alavian, K.N. Post mortem examination of Parkinson’s disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleus. FASEB J., 2019, 33(6), 6957-6961.
[http://dx.doi.org/10.1096/fj.201802628R] [PMID: 30862197]
[107]
Bekar, L.; Libionka, W.; Tian, G.F.; Xu, Q.; Torres, A.; Wang, X.; Lovatt, D.; Williams, E.; Takano, T.; Schnermann, J.; Bakos, R.; Nedergaard, M. Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor. Nat. Med., 2008, 14(1), 75-80.
[http://dx.doi.org/10.1038/nm1693] [PMID: 18157140]
[108]
Vosler, P.S.; Graham, S.H.; Wechsler, L.R.; Chen, J. Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics. Stroke, 2009, 40(9), 3149-3155.
[http://dx.doi.org/10.1161/STROKEAHA.108.543769] [PMID: 19478227]
[109]
Liu, F.; Lu, J.; Manaenko, A.; Tang, J.; Hu, Q. Mitochondria in Ischemic Stroke: New Insight and Implications. Aging Dis., 2018, 9(5), 924-937.
[http://dx.doi.org/10.14336/AD.2017.1126] [PMID: 30271667]
[110]
Doyle, K.P.; Simon, R.P.; Stenzel-Poore, M.P. Mechanisms of ischemic brain damage. Neuropharmacology, 2008, 55(3), 310-318.
[http://dx.doi.org/10.1016/j.neuropharm.2008.01.005] [PMID: 18308346]
[111]
Khoshnam, S.E.; Winlow, W.; Farzaneh, M.; Farbood, Y.; Moghaddam, H.F. Pathogenic mechanisms following ischemic stroke. Neurol. Sci., 2017, 38(7), 1167-1186.
[http://dx.doi.org/10.1007/s10072-017-2938-1] [PMID: 28417216]
[112]
Jia, J.; Jin, H.; Nan, D.; Yu, W.; Huang, Y. New insights into targeting mitochondria in ischemic injury. Apoptosis, 2021, 26(3-4), 163-183.
[http://dx.doi.org/10.1007/s10495-021-01661-5] [PMID: 33751318]
[113]
Ham, P.B., III; Raju, R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog. Neurobiol., 2017, 157, 92-116.
[http://dx.doi.org/10.1016/j.pneurobio.2016.06.006] [PMID: 27321753]
[114]
Broughton, B.R.S.; Reutens, D.C.; Sobey, C.G. Apoptotic mechanisms after cerebral ischemia. Stroke, 2009, 40(5), e331-e339.
[http://dx.doi.org/10.1161/STROKEAHA.108.531632] [PMID: 19182083]
[115]
Zheng, Z.; Zhao, H.; Steinberg, G.K.; Yenari, M.A. Cellular and molecular events underlying ischemia-induced neuronal apoptosis. Drug News Perspect., 2003, 16(8), 497-503.
[http://dx.doi.org/10.1358/dnp.2003.16.8.829348] [PMID: 14668947]
[116]
Sims, N.R.; Muyderman, H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta Mol. Basis Dis., 2010, 1802(1), 80-91.
[http://dx.doi.org/10.1016/j.bbadis.2009.09.003] [PMID: 19751827]
[117]
Galluzzi, L.; Kepp, O.; Kroemer, G. Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol., 2012, 13(12), 780-788.
[http://dx.doi.org/10.1038/nrm3479] [PMID: 23175281]
[118]
Endo, H.; Kamada, H.; Nito, C.; Nishi, T.; Chan, P.H. Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J. Neurosci., 2006, 26(30), 7974-7983.
[http://dx.doi.org/10.1523/JNEUROSCI.0897-06.2006] [PMID: 16870742]
[119]
Hares, M.M.; Downing, R.; Marsh, J. Failure of metronidazole/penicillin oral prophylaxis to prevent amputation stump infection. Lancet, 1980, 315(8176), 1028-1029.
[http://dx.doi.org/10.1016/S0140-6736(80)91465-8] [PMID: 6103352]
[120]
Crack, P.J.; Taylor, J.M. Reactive oxygen species and the modulation of stroke. Free Radic. Biol. Med., 2005, 38(11), 1433-1444.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.01.019] [PMID: 15890617]
[121]
Dharmasaroja, P.A. Fluid Intake Related to Brain Edema in Acute Middle Cerebral Artery Infarction. Transl. Stroke Res., 2016, 7(1), 49-53.
[http://dx.doi.org/10.1007/s12975-015-0439-1] [PMID: 26666449]
[122]
Lee, J.M.; Grabb, M.C.; Zipfel, G.J.; Choi, D.W. Brain tissue responses to ischemia. J. Clin. Invest., 2000, 106(6), 723-731.
[http://dx.doi.org/10.1172/JCI11003] [PMID: 10995780]
[123]
Zhao, H.; Yenari, M.A.; Cheng, D.; Sapolsky, R.M.; Steinberg, G.K. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J. Neurochem., 2003, 85(4), 1026-1036.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01756.x] [PMID: 12716434]
[124]
Barsoum, M.J.; Yuan, H.; Gerencser, A.A.; Liot, G.; Kushnareva, Y.; Gräber, S.; Kovacs, I.; Lee, W.D.; Waggoner, J.; Cui, J.; White, A.D.; Bossy, B.; Martinou, J.C.; Youle, R.J.; Lipton, S.A.; Ellisman, M.H.; Perkins, G.A.; Bossy-Wetzel, E. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J., 2006, 25(16), 3900-3911.
[http://dx.doi.org/10.1038/sj.emboj.7601253] [PMID: 16874299]
[125]
Grohm, J.; Kim, S-W.; Mamrak, U.; Tobaben, S.; Cassidy-Stone, A.; Nunnari, J.; Plesnila, N.; Culmsee, C. Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ., 2012, 19(9), 1446-1458.
[http://dx.doi.org/10.1038/cdd.2012.18] [PMID: 22388349]
[126]
Zhang, L.; He, Z.; Zhang, Q.; Wu, Y.; Yang, X.; Niu, W.; Hu, Y.; Jia, J. Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats. Int. J. Mol. Sci., 2014, 15(3), 4453-4463.
[http://dx.doi.org/10.3390/ijms15034453] [PMID: 24633199]
[127]
Song, M.; Zhou, Y.; Fan, X. Mitochondrial quality and quantity control: mitophagy is a potential therapeutic target for ischemic stroke. Mol. Neurobiol., 2022, 59(5), 3110-3123.
[http://dx.doi.org/10.1007/s12035-022-02795-6] [PMID: 35266113]
[128]
Di, Y.; He, Y.L.; Zhao, T.; Huang, X.; Wu, K.W.; Liu, S.H.; Zhao, Y.Q.; Fan, M.; Wu, L.Y.; Zhu, L.L. Methylene blue reduces acute cerebral ischemic injury via the induction of mitophagy. Mol. Med., 2015, 21(1), 420-429.
[http://dx.doi.org/10.2119/molmed.2015.00038] [PMID: 25998511]
[129]
Liang, J.; Wang, C.; Zhang, H.; Huang, J.; Xie, J.; Chen, N. Exercise-induced benefits for Alzheimer’s disease by stimulating mitophagy and improving mitochondrial function. Front. Aging Neurosci., 2021, 13, 755665.
[http://dx.doi.org/10.3389/fnagi.2021.755665] [PMID: 34658846]
[130]
Raefsky, S.M.; Mattson, M.P. Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic. Biol. Med., 2017, 102, 203-216.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.045] [PMID: 27908782]
[131]
Escribano, L.; Simón, A.M.; Gimeno, E.; Cuadrado-Tejedor, M.; López de Maturana, R.; García-Osta, A.; Ricobaraza, A.; Pérez-Mediavilla, A.; Del Río, J.; Frechilla, D. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology, 2010, 35(7), 1593-1604.
[http://dx.doi.org/10.1038/npp.2010.32] [PMID: 20336061]
[132]
Searcy, J.L.; Phelps, J.T.; Pancani, T.; Kadish, I.; Popovic, J.; Anderson, K.L.; Beckett, T.L.; Murphy, M.P.; Chen, K.C.; Blalock, E.M.; Landfield, P.W.; Porter, N.M.; Thibault, O. Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer’s disease. J. Alzheimers Dis., 2012, 30(4), 943-961.
[http://dx.doi.org/10.3233/JAD-2012-111661] [PMID: 22495349]
[133]
Pinto, M.; Nissanka, N.; Peralta, S.; Brambilla, R.; Diaz, F.; Moraes, C.T. Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation. Mol. Neurodegener., 2016, 11(1), 25.
[http://dx.doi.org/10.1186/s13024-016-0090-7] [PMID: 27038906]
[134]
Zhao, Y.; Lützen, U.; Gohlke, P.; Jiang, P.; Herdegen, T.; Culman, J. Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways. J. Mol. Med. (Berl.), 2021, 99(8), 1073-1083.
[http://dx.doi.org/10.1007/s00109-021-02065-3] [PMID: 33864097]
[135]
Luo, Y.; Yin, W.; Signore, A.P.; Zhang, F.; Hong, Z.; Wang, S.; Graham, S.H.; Chen, J. Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone. J. Neurochem., 2006, 97(2), 435-448.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03758.x] [PMID: 16539667]
[136]
Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol., 2015, 14(8), 795-803.
[http://dx.doi.org/10.1016/S1474-4422(15)00144-1] [PMID: 26116315]
[137]
Risner, M.E.; Saunders, A.M.; Altman, J F B.; Ormandy, G.C.; Craft, S.; Foley, I.M.; Zvartau-Hind, M.E.; Hosford, D.A.; Roses, A.D. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J., 2006, 6(4), 246-254.
[http://dx.doi.org/10.1038/sj.tpj.6500369] [PMID: 16446752]
[138]
Beal, M.F.; Oakes, D.; Shoulson, I.; Henchcliffe, C.; Galpern, W.R.; Haas, R.; Juncos, J.L.; Nutt, J.G.; Voss, T.S.; Ravina, B.; Shults, C.M.; Helles, K.; Snively, V.; Lew, M.F.; Griebner, B.; Watts, A.; Gao, S.; Pourcher, E.; Bond, L.; Kompoliti, K.; Agarwal, P.; Sia, C.; Jog, M.; Cole, L.; Sultana, M.; Kurlan, R.; Richard, I.; Deeley, C.; Waters, C.H.; Figueroa, A.; Arkun, A.; Brodsky, M.; Ondo, W.G.; Hunter, C.B.; Jimenez-Shahed, J.; Palao, A.; Miyasaki, J.M.; So, J.; Tetrud, J.; Reys, L.; Smith, K.; Singer, C.; Blenke, A.; Russell, D.S.; Cotto, C.; Friedman, J.H.; Lannon, M.; Zhang, L.; Drasby, E.; Kumar, R.; Subramanian, T.; Ford, D.S.; Grimes, D.A.; Cote, D.; Conway, J.; Siderowf, A.D.; Evatt, M.L.; Sommerfeld, B.; Lieberman, A.N.; Okun, M.S.; Rodriguez, R.L.; Merritt, S.; Swartz, C.L.; Martin, W.R.W.; King, P.; Stover, N.; Guthrie, S.; Watts, R.L.; Ahmed, A.; Fernandez, H.H.; Winters, A.; Mari, Z.; Dawson, T.M.; Dunlop, B.; Feigin, A.S.; Shannon, B.; Nirenberg, M.J.; Ogg, M.; Ellias, S.A.; Thomas, C.A.; Frei, K.; Bodis-Wollner, I.; Glazman, S.; Mayer, T.; Hauser, R.A.; Pahwa, R.; Langhammer, A.; Ranawaya, R.; Derwent, L.; Sethi, K.D.; Farrow, B.; Prakash, R.; Litvan, I.; Robinson, A.; Sahay, A.; Gartner, M.; Hinson, V.K.; Markind, S.; Pelikan, M.; Perlmutter, J.S.; Hartlein, J.; Molho, E.; Evans, S.; Adler, C.H.; Duffy, A.; Lind, M.; Elmer, L.; Davis, K.; Spears, J.; Wilson, S.; Leehey, M.A.; Hermanowicz, N.; Niswonger, S.; Shill, H.A.; Obradov, S.; Rajput, A.; Cowper, M.; Lessig, S.; Song, D.; Fontaine, D.; Zadikoff, C.; Williams, K.; Blindauer, K.A.; Bergholte, J.; Propsom, C.S.; Stacy, M.A.; Field, J.; Mihaila, D.; Chilton, M.; Uc, E.Y.; Sieren, J.; Simon, D.K.; Kraics, L.; Silver, A.; Boyd, J.T.; Hamill, R.W.; Ingvoldstad, C.; Young, J.; Thomas, K.; Kostyk, S.K.; Wojcieszek, J.; Pfeiffer, R.F.; Panisset, M.; Beland, M.; Reich, S.G.; Cines, M.; Zappala, N.; Rivest, J.; Zweig, R.; Lumina, L.P.; Hilliard, C.L.; Grill, S.; Kellermann, M.; Tuite, P.; Rolandelli, S.; Kang, U.J.; Young, J.; Rao, J.; Cook, M.M.; Severt, L.; Boyar, K. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol., 2014, 71(5), 543-552.
[http://dx.doi.org/10.1001/jamaneurol.2014.131] [PMID: 24664227]
[139]
Xi, Y.; Feng, D.; Tao, K.; Wang, R.; Shi, Y.; Qin, H.; Murphy, M.P.; Yang, Q.; Zhao, G. MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α. Biochim. Biophys. Acta Mol. Basis Dis., 2018, 1864(9)(9 Pt B), 2859-2870.
[http://dx.doi.org/10.1016/j.bbadis.2018.05.018] [PMID: 29842922]
[140]
Ghosh, A.; Langley, M.R.; Harischandra, D.S.; Neal, M.L.; Jin, H.; Anantharam, V.; Joseph, J.; Brenza, T.; Narasimhan, B.; Kanthasamy, A.; Kalyanaraman, B.; Kanthasamy, A.G. Mitoapocynin treatment protects against neuroinflammation and dopaminergic neurodegeneration in a preclinical animal model of Parkinson’s Disease. J. Neuroimmune Pharmacol., 2016, 11(2), 259-278.
[http://dx.doi.org/10.1007/s11481-016-9650-4] [PMID: 26838361]
[141]
Manczak, M.; Mao, P.; Calkins, M.J.; Cornea, A.; Reddy, A.P.; Murphy, M.P.; Szeto, H.H.; Park, B.; Reddy, P.H. Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer’s disease neurons. J. Alzheimers Dis., 2010, 20(s2)(Suppl. 2), S609-S631.
[http://dx.doi.org/10.3233/JAD-2010-100564] [PMID: 20463406]
[142]
Silachev, D.; Plotnikov, E.; Pevzner, I.; Zorova, L.; Balakireva, A.; Gulyaev, M.; Pirogov, Y.; Skulachev, V.; Zorov, D. Neuroprotective effects of mitochondria-targeted plastoquinone in a rat model of neonatal hypoxic–ischemic brain injury. Molecules, 2018, 23(8), 1871.
[http://dx.doi.org/10.3390/molecules23081871] [PMID: 30060443]
[143]
Snow, B.J.; Rolfe, F.L.; Lockhart, M.M.; Frampton, C.M.; O’Sullivan, J.D.; Fung, V.; Smith, R.A.J.; Murphy, M.P.; Taylor, K.M. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov. Disord., 2010, 25(11), 1670-1674.
[http://dx.doi.org/10.1002/mds.23148] [PMID: 20568096]
[144]
Shuaib, A.; Lees, K.R.; Lyden, P.; Grotta, J.; Davalos, A.; Davis, S.M.; Diener, H.C.; Ashwood, T.; Wasiewski, W.W.; Emeribe, U. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med., 2007, 357(6), 562-571.
[http://dx.doi.org/10.1056/NEJMoa070240] [PMID: 17687131]
[145]
Wang, Q.M.; Xu, Y.Y.; Liu, S.; Ma, Z.G. Isradipine attenuates MPTP-induced dopamine neuron degeneration by inhibiting up-regulation of L-type calcium channels and iron accumulation in the substantia nigra of mice. Oncotarget, 2017, 8(29), 47284-47295.
[http://dx.doi.org/10.18632/oncotarget.17618] [PMID: 28521299]
[146]
Gong, L.; Zhang, Q.L.; Zhang, N.; Hua, W.Y.; Huang, Y.X.; Di, P.W.; Huang, T.; Xu, X.S.; Liu, C.F.; Hu, L.F.; Luo, W.F. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: Linking to Akt/GSK3β signaling pathway. J. Neurochem., 2012, 123(5), 876-885.
[http://dx.doi.org/10.1111/jnc.12038] [PMID: 23094836]
[147]
Baek, S.H.; Park, S.J.; Jeong, J.I.; Kim, S.H.; Han, J.; Kyung, J.W.; Baik, S.H.; Choi, Y.; Choi, B.Y.; Park, J.S.; Bahn, G.; Shin, J.H.; Jo, D.S.; Lee, J.Y.; Jang, C.G.; Arumugam, T.V.; Kim, J.; Han, J.W.; Koh, J.Y.; Cho, D.H.; Jo, D.G. Inhibition of Drp1 ameliorates synaptic depression, Aβ deposition, and cognitive impairment in an Alzheimer’s Disease model. J. Neurosci., 2017, 37(20), 5099-5110.
[http://dx.doi.org/10.1523/JNEUROSCI.2385-16.2017] [PMID: 28432138]
[148]
Filichia, E.; Hoffer, B.; Qi, X.; Luo, Y. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Sci. Rep., 2016, 6(1), 32656.
[http://dx.doi.org/10.1038/srep32656] [PMID: 27619562]
[149]
Flippo, K.H.; Lin, Z.; Dickey, A.S.; Zhou, X.; Dhanesha, N.A.; Walters, G.C.; Liu, Y.; Merrill, R.A.; Meller, R.; Simon, R.P.; Chauhan, A.K.; Usachev, Y.M.; Strack, S. Deletion of a neuronal Drp1 activator protects against cerebral ischemia. J. Neurosci., 2020, 40(15), 3119-3129.
[http://dx.doi.org/10.1523/JNEUROSCI.1926-19.2020] [PMID: 32144179]
[150]
Santos, R.X.; Correia, S.C.; Carvalho, C.; Cardoso, S.; Santos, M.S.; Moreira, P.I. Mitophagy in neurodegeneration: An opportunity for therapy? Curr. Drug Targets, 2011, 12(6), 790-799.
[http://dx.doi.org/10.2174/138945011795528813] [PMID: 21269269]
[151]
Zhang, L.; Dai, L.; Li, D. Mitophagy in neurological disorders. J. Neuroinflammation, 2021, 18(1), 297.
[http://dx.doi.org/10.1186/s12974-021-02334-5] [PMID: 34937577]
[152]
Nascimento-dos-Santos, G.; de-Souza-Ferreira, E.; Linden, R.; Galina, A.; Petrs-Silva, H. Mitotherapy: Unraveling a promising treatment for disorders of the central nervous system and other systemic conditions. Cells, 2021, 10(7), 1827.
[http://dx.doi.org/10.3390/cells10071827] [PMID: 34359994]
[153]
Qin, Y.; Jiang, X.; Yang, Q.; Zhao, J.; Zhou, Q.; Zhou, Y. The functions, methods, and mobility of mitochondrial transfer between cells. Front. Oncol., 2021, 11, 672781.
[http://dx.doi.org/10.3389/fonc.2021.672781] [PMID: 34041035]
[154]
Jackson, M.V.; Morrison, T.J.; Doherty, D.F.; McAuley, D.F.; Matthay, M.A.; Kissenpfennig, A.; O’Kane, C.M.; Krasnodembskaya, A.D. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells, 2016, 34(8), 2210-2223.
[http://dx.doi.org/10.1002/stem.2372] [PMID: 27059413]
[155]
Jiang, D.; Gao, F.; Zhang, Y.; Wong, D.S.H.; Li, Q.; Tse, H.; Xu, G.; Yu, Z.; Lian, Q. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Dis., 2016, 7(11), e2467.
[http://dx.doi.org/10.1038/cddis.2016.358] [PMID: 27831562]
[156]
Islam, M.N.; Das, S.R.; Emin, M.T.; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D.J.; Quadri, S.K.; Bhattacharya, S.; Bhattacharya, J. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med., 2012, 18(5), 759-765.
[http://dx.doi.org/10.1038/nm.2736] [PMID: 22504485]
[157]
Hayakawa, K.; Esposito, E.; Wang, X.; Terasaki, Y.; Liu, Y.; Xing, C.; Ji, X.; Lo, E.H. Transfer of mitochondria from astrocytes to neurons after stroke. Nature, 2016, 535(7613), 551-555.
[http://dx.doi.org/10.1038/nature18928] [PMID: 27466127]
[158]
Elliott, R.L.; Jiang, X.P.; Head, J.F. Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res. Treat., 2012, 136(2), 347-354.
[http://dx.doi.org/10.1007/s10549-012-2283-2] [PMID: 23080556]
[159]
Moskowitzova, K.; Shin, B.; Liu, K.; Ramirez-Barbieri, G.; Guariento, A.; Blitzer, D.; Thedsanamoorthy, J.K.; Yao, R.; Snay, E.R.; Inkster, J.A.H.; Orfany, A.; Zurakowski, D.; Cowan, D.B.; Packard, A.B.; Visner, G.A.; del Nido, P.J.; McCully, J.D. Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation. J. Heart Lung Transplant., 2019, 38(1), 92-99.
[http://dx.doi.org/10.1016/j.healun.2018.09.025] [PMID: 30391192]
[160]
Hayashida, K.; Takegawa, R.; Shoaib, M.; Aoki, T.; Choudhary, R.C.; Kuschner, C.E.; Nishikimi, M.; Miyara, S.J.; Rolston, D.M.; Guevara, S.; Kim, J.; Shinozaki, K.; Molmenti, E.P.; Becker, L.B. Mitochondrial transplantation therapy for ischemia reperfusion injury: A systematic review of animal and human studies. J. Transl. Med., 2021, 19(1), 214.
[http://dx.doi.org/10.1186/s12967-021-02878-3] [PMID: 34001191]
[161]
Guariento, A.; Piekarski, B.L.; Doulamis, I.P.; Blitzer, D.; Ferraro, A.M.; Harrild, D.M.; Zurakowski, D.; del Nido, P.J.; McCully, J.D.; Emani, S.M. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg., 2021, 162(3), 992-1001.
[http://dx.doi.org/10.1016/j.jtcvs.2020.10.151] [PMID: 33349443]
[162]
Doulamis, I.P.; Guariento, A.; Duignan, T.; Orfany, A.; Kido, T.; Zurakowski, D.; del Nido, P.J.; McCully, J.D. Mitochondrial transplantation for myocardial protection in diabetic hearts. Eur. J. Cardiothorac. Surg., 2020, 57(5), 836-845.
[http://dx.doi.org/10.1093/ejcts/ezz326] [PMID: 31782771]
[163]
Robicsek, O.; Ene, H.M.; Karry, R.; Ytzhaki, O.; Asor, E.; McPhie, D.; Cohen, B.M.; Ben-Yehuda, R.; Weiner, I.; Ben-Shachar, D. Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophr. Bull., 2018, 44(2), 432-442.
[http://dx.doi.org/10.1093/schbul/sbx077] [PMID: 28586483]
[164]
Clark, M.A.; Shay, J.W. Mitochondrial transformation of mammalian cells. Nature, 1982, 295(5850), 605-607.
[http://dx.doi.org/10.1038/295605a0] [PMID: 7057918]
[165]
Davis, C.O.; Kim, K.Y.; Bushong, E.A.; Mills, E.A.; Boassa, D.; Shih, T.; Kinebuchi, M.; Phan, S.; Zhou, Y.; Bihlmeyer, N.A.; Nguyen, J.V.; Jin, Y.; Ellisman, M.H.; Marsh-Armstrong, N. Transcellular degradation of axonal mitochondria. Proc. Natl. Acad. Sci. USA, 2014, 111(26), 9633-9638.
[http://dx.doi.org/10.1073/pnas.1404651111] [PMID: 24979790]
[166]
Forner, F.; Foster, L.J.; Campanaro, S.; Valle, G.; Mann, M. Quantitative proteomic comparison of rat mitochondria from muscle, heart, and liver. Mol. Cell. Proteomics, 2006, 5(4), 608-619.
[http://dx.doi.org/10.1074/mcp.M500298-MCP200] [PMID: 16415296]
[167]
Cogswell, A.M.; Stevens, R.J.; Hood, D.A. Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am. J. Physiol. Cell Physiol., 1993, 264(2), C383-C389.
[http://dx.doi.org/10.1152/ajpcell.1993.264.2.C383] [PMID: 8383431]
[168]
Preble, J.M.; Pacak, C.A.; Kondo, H.; MacKay, A.A.; Cowan, D.B.; McCully, J.D. Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J. Vis. Exp., 2014, (91), e51682.
[http://dx.doi.org/10.3791/51682] [PMID: 25225817]
[169]
Chang, J.C.; Wu, S.L.; Liu, K.H.; Chen, Y.H.; Chuang, C.S.; Cheng, F.C.; Su, H.L.; Wei, Y.H.; Kuo, S.J.; Liu, C.S. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: Restoration of mitochondria functions and attenuation of 6-hydroxydopamine–induced neurotoxicity. Transl. Res., 2016, 170, 40-56.e3.
[http://dx.doi.org/10.1016/j.trsl.2015.12.003] [PMID: 26730494]
[170]
Gollihue, J.L.; Patel, S.P.; Mashburn, C.; Eldahan, K.C.; Sullivan, P.G.; Rabchevsky, A.G. Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures. J. Neurosci. Methods, 2017, 287, 1-12.
[http://dx.doi.org/10.1016/j.jneumeth.2017.05.023] [PMID: 28554833]
[171]
Masuzawa, A.; Black, K.M.; Pacak, C.A.; Ericsson, M.; Barnett, R.J.; Drumm, C.; Seth, P.; Bloch, D.B.; Levitsky, S.; Cowan, D.B.; McCully, J.D. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol., 2013, 304(7), H966-H982.
[http://dx.doi.org/10.1152/ajpheart.00883.2012] [PMID: 23355340]
[172]
Ramirez-Barbieri, G.; Moskowitzova, K.; Shin, B.; Blitzer, D.; Orfany, A.; Guariento, A.; Iken, K.; Friehs, I.; Zurakowski, D.; del Nido, P.J.; McCully, J.D. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria. Mitochondrion, 2019, 46, 103-115.
[http://dx.doi.org/10.1016/j.mito.2018.03.002] [PMID: 29588218]
[173]
Pollara, J.; Edwards, R.W.; Lin, L.; Bendersky, V.A.; Brennan, T.V. Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction. JCI Insight, 2018, 3(15), e121622.
[http://dx.doi.org/10.1172/jci.insight.121622] [PMID: 30089724]
[174]
Krysko, D.V.; Agostinis, P.; Krysko, O.; Garg, A.D.; Bachert, C.; Lambrecht, B.N.; Vandenabeele, P. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol., 2011, 32(4), 157-164.
[http://dx.doi.org/10.1016/j.it.2011.01.005] [PMID: 21334975]
[175]
Bertero, E.; O’Rourke, B.; Maack, C. Mitochondria do not survive calcium overload during transplantation. Circ. Res., 2020, 126(6), 784-786.
[http://dx.doi.org/10.1161/CIRCRESAHA.119.316291] [PMID: 32078444]
[176]
Al Amir Dache, Z.; Otandault, A.; Tanos, R.; Pastor, B.; Meddeb, R.; Sanchez, C.; Arena, G.; Lasorsa, L.; Bennett, A.; Grange, T.; El Messaoudi, S.; Mazard, T.; Prevostel, C.; Thierry, A.R. Blood contains circulating cell‐free respiratory competent mitochondria. FASEB J., 2020, 34(3), 3616-3630.
[http://dx.doi.org/10.1096/fj.201901917RR] [PMID: 31957088]
[177]
Chang, J.C.; Hoel, F.; Liu, K.H.; Wei, Y.H.; Cheng, F.C.; Kuo, S.J.; Tronstad, K.J.; Liu, C.S. Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation. Sci. Rep., 2017, 7(1), 10710.
[http://dx.doi.org/10.1038/s41598-017-10870-5] [PMID: 28878349]
[178]
Wu, S.; Zhang, A.; Li, S.; Chatterjee, S.; Qi, R.; Segura-Ibarra, V.; Ferrari, M.; Gupte, A.; Blanco, E.; Hamilton, D.J. Polymer functionalization of isolated mitochondria for cellular transplantation and metabolic phenotype alteration. Adv. Sci. (Weinh.), 2018, 5(3), 1700530.
[http://dx.doi.org/10.1002/advs.201700530] [PMID: 29593955]
[179]
Picone, P.; Porcelli, G.; Bavisotto, C.C.; Nuzzo, D.; Galizzi, G.; Biagio, P.L.S.; Bulone, D.; Di Carlo, M. Synaptosomes: New vesicles for neuronal mitochondrial transplantation. J. Nanobiotechnology, 2021, 19(1), 6.
[http://dx.doi.org/10.1186/s12951-020-00748-6] [PMID: 33407593]
[180]
Guariento, A.; Doulamis, I.P.; Duignan, T.; Kido, T.; Regan, W.L.; Saeed, M.Y.; Hoganson, D.M.; Emani, S.M.; Fynn-Thompson, F.; Matte, G.S.; del Nido, P.J.; McCully, J.D. Mitochondrial transplantation for myocardial protection in ex-situ‒perfused hearts donated after circulatory death. J. Heart Lung Transplant., 2020, 39(11), 1279-1288.
[http://dx.doi.org/10.1016/j.healun.2020.06.023] [PMID: 32703639]
[181]
Adlimoghaddam, A.; Benson, T.; Albensi, B.C. Mitochondrial transfusion improves mitochondrial function through up-regulation of mitochondrial complex II protein subunit SDHB in the hippocampus of aged mice. Mol. Neurobiol., 2022. [Epublished of print].
[http://dx.doi.org/10.1007/s12035-022-02937-w] [PMID: 35834060]
[182]
Bobkova, N.V.; Zhdanova, D.Y.; Belosludtseva, N.V.; Penkov, N.V.; Mironova, G.D. Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice. Exp. Biol. Med. (Maywood), 2022, 247(5), 416-425.
[http://dx.doi.org/10.1177/15353702211056866] [PMID: 34727745]
[183]
Nakamura, Y.; Lo, E.H.; Hayakawa, K. Placental mitochondria therapy for cerebral ischemia-reperfusion injury in mice. Stroke, 2020, 51(10), 3142-3146.
[http://dx.doi.org/10.1161/STROKEAHA.120.030152] [PMID: 32819193]
[184]
Pourmohammadi-Bejarpasi, Z.; Roushandeh, A.M.; Saberi, A.; Rostami, M.K.; Toosi, S.M.R.; Jahanian-Najafabadi, A.; Tomita, K.; Kuwahara, Y.; Sato, T.; Roudkenar, M.H. Mesenchymal stem cells-derived mitochondria transplantation mitigates I/R-induced injury, abolishes I/R-induced apoptosis, and restores motor function in acute ischemia stroke rat model. Brain Res. Bull., 2020, 165, 70-80.
[http://dx.doi.org/10.1016/j.brainresbull.2020.09.018] [PMID: 33010349]
[185]
Huang, P.J.; Kuo, C.C.; Lee, H.C.; Shen, C.I.; Cheng, F.C.; Wu, S.F.; Chang, J.C.; Pan, H.C.; Lin, S.Z.; Liu, C.S.; Su, H.L. Transferring Xenogenic mitochondria provides neural protection against ischemic stress in ischemic rat brains. Cell Transplant., 2016, 25(5), 913-927.
[http://dx.doi.org/10.3727/096368915X689785] [PMID: 26555763]
[186]
Xie, Q.; Zeng, J.; Zheng, Y.; Li, T.; Ren, J.; Chen, K.; Zhang, Q.; Xie, R.; Xu, F.; Zhu, J. Mitochondrial transplantation attenuates cerebral ischemia-reperfusion injury: Possible involvement of mitochondrial component separation. Oxid. Med. Cell. Longev., 2021, 2021, 1-21.
[http://dx.doi.org/10.1155/2021/1006636] [PMID: 34849186]

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      • 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) 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 >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59467608 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59467608) limit 1
      12.24msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59467608
      • 1: 59467608
      • 2: 59467608
      • 3: 59467608
      • 4: 59467608
      • 5: 59467608
      • 6: 59467608
      • 7: 59467608
      • 8: 59467608
      • 9: 59467608
      • 10: 59467608
      • 11: 59467608
      • 12: 59467608
      • 13: 59467608
      • 14: 59467608
      • 15: 59467608
      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=126219
      1.87msalphaeurekaselec_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` = 26 limit 1
      1.18msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 26
      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`
      1.57msalphaeurekaselec_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
      1.3msalphaeurekaselec_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`
      2.15msalphaeurekaselec_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
      1.97msalphaeurekaselec_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` = '126219'
      1.72msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 126219
      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` = '126219'
      5.84msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 126219
      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` = '126219' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.88msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 126219
      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
      440μsalphaeurekaselec_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
      810μsalphaeurekaselec_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
      40.76msalphaeurekaselec_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
      8.64msalphaeurekaselec_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
      7.71msalphaeurekaselec_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` = 126219 limit 1
      300μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 126219
      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 = 126219 and content_type = 'article' order by status desc limit 1
      290μsalphaeurekaselec_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` = 208641 limit 1
      240μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 208641
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      310μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CN' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      350μsalphaeurekaselec_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 = '126219' 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) )
      460μsalphaeurekaselec_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 = '12409' 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) )
      390μsalphaeurekaselec_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 = '3342' 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) )
      370μsalphaeurekaselec_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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3342) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3342) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3342)
      9.31msalphaeurekaselec_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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12409) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12409) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12409)
      980μsalphaeurekaselec_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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 126219) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 126219) 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 <= 59467608 and j.to_ip >=59467608 )) and ((j.from_date <= 1740527593 and j.to_date >= 1740527593 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 126219)
      930μsalphaeurekaselec_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` < '1100' and is_uploaded = 1 and issue_id = 12409 order by cast(first_page as SIGNED) desc limit 1
      820μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1100
      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` > '1116' and is_uploaded = 1 and issue_id = 12409 order by cast(first_page as SIGNED) asc limit 1
      740μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1116
      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'
      270μsalphaeurekaselec_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
      320μsalphaeurekaselec_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` = 126219 limit 1
      3.94msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 126219
      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` <= 1740527593 and `b`.`banner_to_date` >= 1740527593 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.66msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1740527593
      • 4: 1740527593
      • 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` <= 1740527593 and `b`.`banner_to_date` >= 1740527593 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.63msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1740527593
      • 4: 1740527593
      • 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='1ead42af2c659455e770cc5c1ce3ede4'
      350μsalphaeurekaselec_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
        EZkPpbBGJAchOenqhc6oDeLRJZx3HwW5gJxWUBoM
        uc_cart_id
        1ead42af2c659455e770cc5c1ce3ede4
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/article/126219" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/126219
        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:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6InVSNVlSNDFFUzdlOFE1M2NIYlIrMEE9PSIsInZhbHVlIjoiMHNxeGlmQllVL2hJS004YndPUmtBOU83RzJiTytuYnowSjNGeHBHU21oVT0iLCJtYWMiOiI3MDQ5YmU4MzY2OTk2YThmYWVjMzJjMWE0MjFkYzAwMmYxZjA5YTc5NzAxYmY1ODhlYzc0OTIzMzI4OTI4YjRjIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6InVSNVlSNDFFUzdlOFE1M2NIYlIrMEE9PSIsInZhbHVlIjoiMHNxeGlmQllVL2hJS004YndPUmtBOU83RzJiTytuYnowSjNGeHBHU21oVT0iLCJtYWMiOiI3MDQ5YmU4MzY2OTk2" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "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" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
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