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Shu Y, Hong W, Jiaoying L, Zhu X. Exploring the Association of dietary index for gut microbiota with Parkinson's disease and depression: Insights from NHANES. J Affect Disord 2025:119461. [PMID: 40419161 DOI: 10.1016/j.jad.2025.119461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 05/20/2025] [Accepted: 05/23/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND Depression and Parkinson's disease (PD) are important public health issues strongly associated with diet and gut microbiota. The aim of this study was to investigate the association of the dietary index for gut microbiota (DI-GM) with Parkinson's disease and depression. METHODS This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) database (2007-2020), with a total of 26,473 participants aged 18-80 years, weighted to represent 256 million US adults. Dietary recall data were used to calculate the DI-GM. Weighted logistic regression was used to analyze the relationship between the DI-GM and depression and PD, and to explore the potential mediating role of the DI-GM in depression and PD. Subgroup analyses and restricted cubic spline (RCS) analyses were also performed. RESULTS The weighted prevalence of PD combined with depression was approximately 22.99 %. We found a possible inverted U-shaped relationship between DI-GM and depression. Higher DI-GM scores were associated with a lower risk of PD (OR = 0.84, 95 % CI (0.75,0.94)). Mediation modelling indicated no significant role for DI-GM in the relationship between depression and PD. The RCS showed a non-linear association between DI-GM and PD. CONCLUSIONS A dose-dependent nonlinear association was identified between the DI-GM and PD. Preliminary evidence suggests a potential inverted U-shaped DI-GM-depression relationship requiring validation. This suggests that focusing on DI-GM may be helpful in studying PD and depression.
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Affiliation(s)
- Yanping Shu
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang, China
| | - Wei Hong
- Department of Neurology, Taizhou People's Hospital Affiliated to Nanjing Medical University, China
| | - Liu Jiaoying
- Department of Psychiatry of Women and Children, The Second People's Hospital of Guizhou Province, Guiyang, China
| | - Xianlin Zhu
- Department of Clinical Psychology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
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Zhang L, Yan YB, Tong L, Chen R, Zhang Y. Colorimetric/fluorescent dual-channel recognition of L-tryptophan with rapid and visual sensing of HNQB-Cu(II) in zebrafish and nuts. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 341:126397. [PMID: 40381233 DOI: 10.1016/j.saa.2025.126397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 05/08/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
In this paper, a fluorescent probe HNQB-Cu(II) was designed and synthesized for the rapid and intuitive detection of L-tryptophan. HNQB-Cu(II) was prepared from 2-hydroxy-N'-(quinolin-2-ylmethylene)benzohydrazide and copper(II) nitrate. The weak interaction forces of the HNQB-Cu(II) probe were studied by DFT calculation, electrostatic filament analysis, interaction region indicator (IRI) research and molecular freedom analysis. Then the fluorescence full scan and anti-interference experiments were carried out for 20 amino acids, and the test results manifested that the HNQB-Cu(II) probe has good selective identification performance and anti-interference ability for L-tryptophan. The sensor displayed good advantages in terms of recognition L-tryptophan with high specificity and selectivity, good time stability and low limit of detection (LOD = 3.9466 μM, R2 = 0.97802) in DMF. Combined HNQB-Cu(II) and paper a strip to detect L-tryptophan through a color change. Interestingly, HNQB-Cu(II) exhibits a superior fluorescence effect caudal fin of zebrafish a fluorescence microscope. In order to further research the application of check and measure L-tryptophan, the content of L-tryptophan in three kinds of nuts (pumpkin seeds, walnuts and peanuts) was quantitatively analyzed. The results show that HNQB-Cu(II) can reveal the L-tryptophan content more conveniently and quickly.
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Affiliation(s)
- Li Zhang
- School of Chemistry and Chemical Engineering, Lanzhou City University, Lanzhou 730000, PR China.
| | - Yi-Bin Yan
- School of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, PR China
| | - Li Tong
- School of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, PR China
| | - Rui Chen
- School of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, PR China
| | - Yang Zhang
- School of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, PR China.
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3
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Jia H, Liu M, Jiang H, Qiao Z, Ren K, Du X, Chen X, Jiao Q, Che F. Repurposing of epalrestat for neuroprotection in parkinson's disease via activation of the KEAP1/Nrf2 pathway. J Neuroinflammation 2025; 22:125. [PMID: 40301912 PMCID: PMC12042445 DOI: 10.1186/s12974-025-03455-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Epalrestat (EPS), an aldose reductase inhibitor, is used to alleviate peripheral nerve disorder of diabetic patients in clinical therapy. Even though EPS exerted effects in central nervous system diseases, the neuroprotection and underlying molecular mechanism in neurodegenerative diseases, especially Parkinson's disease (PD), remains obscure. Our study aimed to investigate the potential of EPS suppressed PD progression both in vivo and in vitro. METHODS We used 1-methyl-4-phenylpyridillium ion (MPP+)-treated PD cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice to investigate the protective function and molecular mechanism of EPS in PD. EPS was administered three times daily through oral route 3 days before model establishment for 5 consecutive days. Behavioral manifestation of mice was conducted using open field test, rotarod test and CatWalk gait analysis. Immunofluorescence was used to detect dopaminergic (DAergic) neurons survival in the substantia nigra. Subsequently, oxidative stress, mitochondrial function and KEAP1/Nrf2 signaling pathway in PD models were detected through molecular biology methods to assess the effect and downstream mechanisms of EPS on PD. Molecular docking, surface plasmon resonance and cellular thermal shift assay were used to verify the direct binding of EPS and KEAP1. RESULTS We found that EPS exhibited potent antiparkinsonian activity in PD models both in vivo and in vitro. PD models treated with EPS manifested alleviated oxidative stress and mitochondrial dysfunction. Furthermore, we found EPS activated the Nrf2 signaling pathway which contributed to DAergic neurons survival in PD models. Particularly, we firstly confirmed that EPS competitively binds to KEAP1 and enhanced its degradation, thereby activating the Nrf2 signaling pathway. CONCLUSIONS Collectively, EPS attenuates oxidative stress and mitochondrial dysfunction by directly binding KEAP1 to activate the KEAP1/Nrf2 signaling pathway, further reducing DAergic neurons damage. These findings suggest that EPS has great potential to become a therapeutic for PD as a clinically effective and safe medicine.
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Affiliation(s)
- Huafang Jia
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Mengru Liu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
- Shandong Key Laboratory of Neurorehabilitation, School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao, 266113, China
| | - Zhen Qiao
- Shandong Key Laboratory of Neurorehabilitation, School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao, 266113, China
| | - Kaiyue Ren
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266071, China.
| | - Fengyuan Che
- Shandong Provincial Clinical Research Center for Geriatric Diseases; Key Laboratory of Neurophysiology, Health Commission of Shandong Province; Linyi Key Laboratory of Neurophysiology, Department of Neurology, Linyi People's Hospital, Linyi, 276000, China.
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Armeli F, Mengoni B, Laskin DL, Businaro R. Interplay among Oxidative Stress, Autophagy, and the Endocannabinoid System in Neurodegenerative Diseases: Role of the Nrf2- p62/SQSTM1 Pathway and Nutraceutical Activation. Curr Issues Mol Biol 2024; 46:6868-6884. [PMID: 39057052 PMCID: PMC11276139 DOI: 10.3390/cimb46070410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/27/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The onset of neurodegenerative diseases involves a complex interplay of pathological mechanisms, including protein aggregation, oxidative stress, and impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disorders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox signaling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a critical antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading altered cell components. The interaction among p62/SQSTM1, Nrf2, and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2-p62/SQSTM1 pathway holds promise for therapeutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, this review explores the potential synergy between the endocannabinoid system and Nrf2 signaling for neuroprotection. Further research is needed to elucidate the involved molecular mechanisms and develop effective therapeutic strategies against neurodegeneration.
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Affiliation(s)
- Federica Armeli
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, 79, 04100 Latina, Italy; (F.A.); (B.M.)
| | - Beatrice Mengoni
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, 79, 04100 Latina, Italy; (F.A.); (B.M.)
| | - Debra L. Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA;
| | - Rita Businaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, 79, 04100 Latina, Italy; (F.A.); (B.M.)
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Vilar-Pereira G, Gibaldi D, Castaño-Barrios L, da Silva AA, Resende Pereira I, Cruz Moreira O, Britto C, Mata dos Santos HA, de Oliveira Lopes R, Wanderley Tinoco L, Oliveira W, Lannes-Vieira J. The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi. PLoS Negl Trop Dis 2024; 18:e0012199. [PMID: 38776344 PMCID: PMC11149870 DOI: 10.1371/journal.pntd.0012199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 06/04/2024] [Accepted: 05/06/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. METHODOLOGY/PRINCIPAL FINDINGS In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. CONCLUSION/SIGNIFICANCE We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.
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Affiliation(s)
- Glaucia Vilar-Pereira
- Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil
| | - Daniel Gibaldi
- Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil
| | - Leda Castaño-Barrios
- Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil
| | - Andrea Alice da Silva
- Laboratório Multidisciplinar de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil
| | - Isabela Resende Pereira
- Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil
| | - Otacílio Cruz Moreira
- Laboratório de Virologia e Parasitologia Molecular, IOC/Fiocruz, Rio de Janeiro, Brazil
| | - Constança Britto
- Laboratório de Biologia Molecular e Doenças Endêmicas, IOC/Fiocruz, Rio de Janeiro, Brazil
| | - Hílton Antônio Mata dos Santos
- Escola de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratório de Análise e Desenvolvimento de Inibidores Enzimáticos, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Raquel de Oliveira Lopes
- Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratório Multiusuário de Análises por Ressonância Magnética Nuclear (LAMAR), Instituto de Pesquisas de Produtos Naturais (IPPN), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luzineide Wanderley Tinoco
- Laboratório Multiusuário de Análises por Ressonância Magnética Nuclear (LAMAR), Instituto de Pesquisas de Produtos Naturais (IPPN), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Wilson Oliveira
- Ambulatório de Doença de Chagas e Insuficiência Cardíaca, Pronto Socorro Cardiológico de Pernambuco (PROCAPE)/Universidade de Pernambuco, Recife, Brazil
| | - Joseli Lannes-Vieira
- Laboratório de Biologia das Interações, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil
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Sharma M, Aggarwal N, Mishra J, Panda JJ. Neuroglia targeting nano-therapeutic approaches to rescue aging and neurodegenerating brain. Int J Pharm 2024; 654:123950. [PMID: 38430951 DOI: 10.1016/j.ijpharm.2024.123950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/12/2024] [Accepted: 02/25/2024] [Indexed: 03/05/2024]
Abstract
Despite intense efforts at the bench, the development of successful brain-targeting therapeutics to relieve malicious neural diseases remains primitive. The brain, being a beautifully intricate organ, consists of heterogeneous arrays of neuronal and glial cells. Primarily acting as the support system for neuronal functioning and maturation, glial cells have been observed to be engaged more apparently in the progression and worsening of various neural pathologies. The diseased state is often related to metabolic alterations in glial cells, thereby modulating their physiological homeostasis in conjunction with neuronal dysfunction. A plethora of data indicates the effect of oxidative stress, protein aggregation, and DNA damage in neuroglia impairments. Still, a deeper insight is needed to gain a conflict-free understanding in this arena. As a consequence, glial cells hold the potential to be identified as promising targets for novel therapeutic approaches aimed at brain protection. In this review, we describe the recent strides taken in the direction of understanding the impact of oxidative stress, protein aggregation, and DNA damage on neuroglia impairment and neuroglia-directed nanotherapeutic approaches to mitigate the burden of various neural disorders.
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Affiliation(s)
- Manju Sharma
- Institute of Nano Science and Technology, Mohali, Punjab 140306, India
| | - Nidhi Aggarwal
- Institute of Nano Science and Technology, Mohali, Punjab 140306, India
| | - Jibanananda Mishra
- School of Biosciences, RIMT University, Mandi Gobindgarh, Punjab 147301, India.
| | - Jiban Jyoti Panda
- Institute of Nano Science and Technology, Mohali, Punjab 140306, India.
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Essawy Essawy A, Abou-ElNaga OA, Mehanna RA, Badae NM, Elsawy ES, Soffar AA. Comparing the effect of intravenous versus intracranial grafting of mesenchymal stem cells against parkinsonism in a rat model: Behavioral, biochemical, pathological and immunohistochemical studies. PLoS One 2024; 19:e0296297. [PMID: 38349932 PMCID: PMC10863851 DOI: 10.1371/journal.pone.0296297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/10/2023] [Indexed: 02/15/2024] Open
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1β, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method.
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Affiliation(s)
- Amina Essawy Essawy
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | | | - Radwa Ali Mehanna
- Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Noha Mohammed Badae
- Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Eman Sheta Elsawy
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Song Z, Wu Z, Luo R, He C, Li Z, Yang M, Yu W, He J, Deng S, Cheng S. Identification of tryptophan metabolism-related genes in immunity and immunotherapy in Alzheimer's disease. Aging (Albany NY) 2023; 15:13077-13099. [PMID: 37988184 DOI: 10.18632/aging.205220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/15/2023] [Indexed: 11/23/2023]
Abstract
Recent studies have highlighted the significant involvement of tryptophan metabolism in the pathogenesis of Alzheimer's disease (AD). However, a comprehensive investigation of the precise role of tryptophan metabolism in the context of AD is still lacking. This study employed a bioinformatics approach to identify and validate potential tryptophan metabolism-related genes (TrpMgs) associated with AD. The discovery of TrpMgs was facilitated through the intersection of the Weighted Gene Co-expression Network Analysis (WGCNA) test and 17 known tryptophan metabolism pathways. Subsequently, the putative biological functions and pathways of the TrpMgs were elucidated using Gene Set Variation Analysis (GSVA). Furthermore, the Least Absolute Shrinkage and Selection Operator (LASSO) method was applied to identify hub genes and evaluate the diagnostic efficiency of the 5 TrpMgs in distinguishing AD. The relationship between hub TrpMgs and clinical characteristics was also investigated. Finally, in vivo verification of the five TrpMgs was performed using APP/PS1 mice. We identified 5 TrpMgs associated with AD, including propionyl-CoA carboxylase subunit beta (PCCB), TEA Domain Transcription Factor 1 (TEAD1), Phenylalanyl-TRNA Synthetase Subunit Beta (FARSB), Neurofascin (NFASC), and Ezrin (EZR). Among these genes, PCCB, FARSB, NFASC, and TEAD1 showed correlations with age. In the hippocampus of APP/PS1 mice, we observed down-regulation of FARSB, PCCB, and NFASC mRNA expressions. Furthermore, PCCB and NFASC protein expressions were also down-regulated in the cerebral cortex and hippocampus of APP/PS1 mice. Our study paves the way for future research aimed at unraveling the intricate mechanisms underlying tryptophan metabolism dysregulation in AD and its therapeutic implications.
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Affiliation(s)
- Zhenyan Song
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Zixuan Wu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Rongsiqing Luo
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Chunxiang He
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Ze Li
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Miao Yang
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Wenjing Yu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Jiawei He
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Sisi Deng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
| | - Shaowu Cheng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
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Eva L, Pleș H, Covache-Busuioc RA, Glavan LA, Bratu BG, Bordeianu A, Dumitrascu DI, Corlatescu AD, Ciurea AV. A Comprehensive Review on Neuroimmunology: Insights from Multiple Sclerosis to Future Therapeutic Developments. Biomedicines 2023; 11:2489. [PMID: 37760930 PMCID: PMC10526343 DOI: 10.3390/biomedicines11092489] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/02/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
This review delves into neuroimmunology, focusing on its relevance to multiple sclerosis (MS) and potential treatment advancements. Neuroimmunology explores the intricate relationship between the immune system and the central nervous system (CNS). Understanding these mechanisms is vital for grasping the pathophysiology of diseases like MS and for devising innovative treatments. This review introduces foundational neuroimmunology concepts, emphasizing the role of immune cells, cytokines, and blood-brain barrier in CNS stability. It highlights how their dysregulation can contribute to MS and discusses genetic and environmental factors influencing MS susceptibility. Cutting-edge research methods, from omics techniques to advanced imaging, have revolutionized our understanding of MS, offering valuable diagnostic and prognostic tools. This review also touches on the intriguing gut-brain axis, examining how gut microbiota impacts neuroimmunological processes and its potential therapeutic implications. Current MS treatments, from immunomodulatory drugs to disease-modifying therapies, are discussed alongside promising experimental approaches. The potential of personalized medicine, cell-based treatments, and gene therapy in MS management is also explored. In conclusion, this review underscores neuroimmunology's significance in MS research, suggesting that a deeper understanding could pave the way for more tailored and effective treatments for MS and similar conditions. Continued research and collaboration in neuroimmunology are essential for enhancing patient outcomes.
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Affiliation(s)
- Lucian Eva
- Clinical Emergency Hospital “Prof. Dr. Nicolae Oblu”, 700309 Iasi, Romania;
| | - Horia Pleș
- Department of Neurosurgery, Centre for Cognitive Research in Neuropsychiatric Pathology (NeuroPsy-Cog), “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Razvan-Adrian Covache-Busuioc
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - Luca Andrei Glavan
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - Bogdan-Gabriel Bratu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - Andrei Bordeianu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - David-Ioan Dumitrascu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - Antonio Daniel Corlatescu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 București, Romania; (L.A.G.); (B.-G.B.); (A.B.); (D.-I.D.); (A.D.C.); (A.V.C.)
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10
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Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis. Int J Mol Sci 2023; 24:ijms24032922. [PMID: 36769239 PMCID: PMC9917916 DOI: 10.3390/ijms24032922] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.
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11
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Fiore NJ, Tamer-Mahoney JD, Beheshti A, Nieland TJF, Kaplan DL. 3D biocomposite culture enhances differentiation of dopamine-like neurons from SH-SY5Y cells: A model for studying Parkinson's disease phenotypes. Biomaterials 2022; 290:121858. [PMID: 36272218 DOI: 10.1016/j.biomaterials.2022.121858] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/30/2022] [Accepted: 10/09/2022] [Indexed: 01/01/2023]
Abstract
Studies of underlying neurodegenerative processes in Parkinson's Disease (PD) have traditionally utilized cell cultures grown on two-dimensional (2D) surfaces. Biomimetic three-dimensional (3D) cell culture platforms have been developed to better emulate features of the brain's natural microenvironment. We here use our bioengineered brain-like tissue model, composed of a silk-hydrogel composite, to study the 3D microenvironment's contributions on the development and performance of dopaminergic-like neurons (DLNs). Compared with 2D culture, SH-SY5Y cells differentiated in 3D microenvironments were enriched for DLNs concomitant with a reduction in proliferative capacity during the neurodevelopmental process. Additionally, the 3D DLN cultures were more sensitive to oxidative stresses elicited by the PD-related neurotoxin 1-methyl-4-phenylpyridinium (MPP). MPP induced transcriptomic profile changes specific to 3D-differentiated DLN cultures, replicating the dysfunction of neuronal signaling pathways and mitochondrial dynamics implicated in PD. Overall, this physiologically-relevant 3D platform resembles a useful tool for studying dopamine neuron biology and interrogating molecular mechanisms underlying neurodegeneration in PD.
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Affiliation(s)
- Nicholas J Fiore
- Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.
| | | | - Afshin Beheshti
- KBR, NASA Ames Research Center, Moffett Field, CA, 94035, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
| | | | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.
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12
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Cai H, Wang Z, Tang W, Ke X, Zhao E. Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells. Front Genet 2022; 13:970699. [PMID: 36110206 PMCID: PMC9468880 DOI: 10.3389/fgene.2022.970699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/11/2022] [Indexed: 11/22/2022] Open
Abstract
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular functions, such as cell proliferation, metabolism, autophagy, survival and cytoskeletal organization. Furthermore, mTOR is made up of three multisubunit complexes, mTOR complex 1, mTOR complex 2, and putative mTOR complex 3. In recent years, increasing evidence has suggested that mTOR plays important roles in the differentiation and immune responses of mesenchymal stem cells (MSCs). In addition, mTOR is a vital regulator of pivotal cellular and physiological functions, such as cell metabolism, survival and ageing, where it has emerged as a novel therapeutic target for ageing-related diseases. Therefore, the mTOR signaling may develop a large impact on the treatment of ageing-related diseases with MSCs. In this review, we discuss prospects for future research in this field.
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Affiliation(s)
- Huarui Cai
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Zhongze Wang
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Wenhan Tang
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
| | - Xiaoxue Ke
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
- *Correspondence: Xiaoxue Ke, ; Erhu Zhao,
| | - Erhu Zhao
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
- *Correspondence: Xiaoxue Ke, ; Erhu Zhao,
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13
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A review on neurodegenerative diseases associated with oxidative stress and mitochondria. Int J Health Sci (Qassim) 2022. [DOI: 10.53730/ijhs.v6ns1.6130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Alzheimer's disease, Parkinson's disease, and other neurological diseases afflict people of all ages. Neuronal loss and cognitive dysfunction are common symptoms of these disorders. Overproduction of reactive oxygen species has been demonstrated to aggravate disease progression in previous investigations (ROS). Because of the large quantities of polyunsaturated fatty acids in their membranes and their fast oxygen consumption rate, neurons are especially susceptible to oxidative damage. The molecular aetiology of neurodegeneration produced by changes in redox balance has not yet been established. New antioxidants have shown considerable potential in modifying disease characteristics. For the treatment of Alzheimer's disease and other neurodegenerative illnesses such as Parkinson's disease, ALS and spinocerebellar ataxia and Huntington's disease, antioxidant-based therapies are examined extensively in the literature.
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14
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Demirci-Çekiç S, Özkan G, Avan AN, Uzunboy S, Çapanoğlu E, Apak R. Biomarkers of Oxidative Stress and Antioxidant Defense. J Pharm Biomed Anal 2021; 209:114477. [PMID: 34920302 DOI: 10.1016/j.jpba.2021.114477] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/27/2021] [Accepted: 11/11/2021] [Indexed: 12/13/2022]
Abstract
A number of reactive oxygen and nitrogen species are produced during normal metabolism in human body. These species can be both radical and non-radical and have varying degrees of reactivity. Although they have some important functions in the human body, such as contributing to signal transmission and the immune system, their presence must be balanced by the antioxidant defense system. The human body has an excellent intrinsic enzymatic antioxidant system in addition to different non-enzymatic antioxidants having small molecular masses. An extrinsic source of antioxidants are foodstuffs such as fruits, vegetables, herbs and spices, mostly rich in polyphenols. When the delicate biochemical balance between oxidants and antioxidants is disturbed in favor of oxidants, "oxidative stress" conditions emerge, under which reactive species can cause oxidative damage to biomacromolecules such as proteins, carbohydrates, lipids and DNA. This oxidative damage is often associated with cancer, aging, and neurodegenerative disorders. Because reactive species are extremely short-lived, it is almost impossible to measure their concentrations directly. Although there are certain methods such as ESR / EPR that serve this purpose, they have some disadvantages and are quite costly systems. Therefore, products generated from oxidative damage of proteins, lipids and DNA are often used to quantify the extent of oxidative damage rather than direct measurement of reactive species. These oxidative damage products are usually known as biomarkers. Determination of the concentrations of these biomarkers and changes in the concentration of protective antioxidants can provide useful information for avoiding certain diseases and keep healthy conditions.
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Affiliation(s)
- Sema Demirci-Çekiç
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey
| | - Gülay Özkan
- Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical Uviversity, Istanbul, Turkey
| | - Aslı Neslihan Avan
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey
| | - Seda Uzunboy
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey
| | - Esra Çapanoğlu
- Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical Uviversity, Istanbul, Turkey.
| | - Reşat Apak
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpasa, Avcilar, 34320 Istanbul, Turkey; Turkish Academy of Sciences (TUBA), Vedat Dalokay St. No. 112, Cankaya, 06670 Ankara, Turkey.
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15
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Li C, Wang R, Zhang Y, Hu C, Ma Q. PIAS3 suppresses damage in an Alzheimer's disease cell model by inducing the STAT3-associated STAT3/Nestin/Nrf2/HO-1 pathway. Mol Med 2021; 27:150. [PMID: 34837964 PMCID: PMC8626961 DOI: 10.1186/s10020-021-00410-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 11/09/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD), the most common form of dementia, is caused by the degeneration of the central nervous system (CNS). A previous study reported that signal transducer and activator of transcription 3 (STAT3) is activated during AD development; nonetheless, the related mechanism remains unknown. Thus, this study used a cell model to explore whether and how the protein inhibitor of activated STAT3 (PIAS3) is involved in AD development. METHODS Cerebrospinal fluid (CSF) specimens of 30 patients with AD and 10 normal participants were included in this study. SH-SY5Y cells were used to constructed AD model. Relevant indices were then detected and analyzed. RESULTS The results showed that compared with the control group, PIAS3 expression was substantially decreased in patients with AD and amyloid beta (Aβ)-treated SH-SY5Y cells. PIAS3 overexpression was able to reverse the detrimental effects of Aβ treatment on cell survival and growth. Further, it could also ameliorate apoptosis and oxidative stress in Aβ-treated SH-SY5Y cells. Additionally, PIAS3 was shown to reduce the activated form of STAT3 and increase the activity of the downstream Nestin/nuclear factor erythroid 2-related factor/heme oxygenase-1 pathway. CONCLUSIONS STAT3 reactivation by colivelin treatment negated the influence of PIAS3 on the survival, growth, apoptosis, and oxidative stress of Aβ-treated SH-SY5Y cells.
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Affiliation(s)
- Chen Li
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Ruili Wang
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Youyou Zhang
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Chunting Hu
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Qiaoya Ma
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, 710004 Shaanxi People’s Republic of China
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16
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Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells 2021; 10:cells10071603. [PMID: 34206739 PMCID: PMC8306609 DOI: 10.3390/cells10071603] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients’ lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process.
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17
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Behl T, Kaur I, Sehgal A, Singh S, Bhatia S, Al-Harrasi A, Zengin G, Bumbu AG, Andronie-Cioara FL, Nechifor AC, Gitea D, Bungau AF, Toma MM, Bungau SG. The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson's Disorder and Therapeutic Implications. Int J Mol Sci 2021; 22:6737. [PMID: 34201647 PMCID: PMC8268239 DOI: 10.3390/ijms22136737] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson's disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA-which antagonizes QUIN actions-primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.
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Affiliation(s)
- Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Ishnoor Kaur
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Aayush Sehgal
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Sukhbir Singh
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Gurugram, Haryana 122412, India;
- Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616 Birkat Al Mouz, Nizwa 611, Oman;
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616 Birkat Al Mouz, Nizwa 611, Oman;
| | - Gokhan Zengin
- Department of Biology, Faculty of Science, Selcuk University Campus, Konya 42130, Turkey;
| | - Adrian Gheorghe Bumbu
- Department of Surgical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Felicia Liana Andronie-Cioara
- Department of Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Aurelia Cristina Nechifor
- Analytical Chemistry and Environmental Engineering Department, Polytechnic University of Bucharest, 011061 Bucharest, Romania;
| | - Daniela Gitea
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
| | | | - Mirela Marioara Toma
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
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18
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Liu C, Wang W, Li H, Liu J, Zhang P, Cheng Y, Qin X, Hu Y, Wei Y. The neuroprotective effects of isoquercitrin purified from apple pomace by high-speed countercurrent chromatography in the MPTP acute mouse model of Parkinson's disease. Food Funct 2021; 12:6091-6101. [PMID: 34047315 DOI: 10.1039/d1fo00843a] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Parkinson's disease is the second most common neurodegenerative disease. Researchers have shown that oxidative stress and apoptosis play an important role in the Parkinson's disease process. Isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is a natural flavonol compound and one of the main active ingredients of agricultural waste apple pomace. Increasing evidence indicates that this compound possesses anti-oxidation, anti-aging, and anti-inflammation properties. In this study, isoquercitrin was purified from apple pomace by high-speed countercurrent chromatography and its neuroprotective effect on Parkinson's disease was investigated in MPTP-induced acute mouse models. It was found that isoquercitrin ameliorated the animal behaviors against MPTP-induced neurotoxicity, mitigated the loss of dopamine neurons induced by MPTP, increased tyrosine hydroxylase and dopamine transporter expression, reduced the pro-apoptotic signaling molecule bax expression and inhibited MPTP-triggered oxidative stress. Our results demonstrated that isoquercitrin has protective effects on the MPTP subacute model mouse, which might be partially mediated through the actions of anti-oxidation and anti-apoptosis. Isoquercitrin might be a new promising protective drug for the improvement of Parkinson's disease.
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Affiliation(s)
- Cong Liu
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Wenjuan Wang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Hao Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Jiangang Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Peng Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yong Cheng
- Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China
| | - Xiaoyan Qin
- Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China
| | - Yang Hu
- Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China
| | - Yun Wei
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
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19
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Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases. Cells 2020; 9:cells9102183. [PMID: 32998318 PMCID: PMC7601929 DOI: 10.3390/cells9102183] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022] Open
Abstract
Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.
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20
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Korshunov KS, Blakemore LJ, Trombley PQ. Illuminating and Sniffing Out the Neuromodulatory Roles of Dopamine in the Retina and Olfactory Bulb. Front Cell Neurosci 2020; 14:275. [PMID: 33110404 PMCID: PMC7488387 DOI: 10.3389/fncel.2020.00275] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/04/2020] [Indexed: 01/28/2023] Open
Abstract
In the central nervous system, dopamine is well-known as the neuromodulator that is involved with regulating reward, addiction, motivation, and fine motor control. Yet, decades of findings are revealing another crucial function of dopamine: modulating sensory systems. Dopamine is endogenous to subsets of neurons in the retina and olfactory bulb (OB), where it sharpens sensory processing of visual and olfactory information. For example, dopamine modulation allows the neural circuity in the retina to transition from processing dim light to daylight and the neural circuity in the OB to regulate odor discrimination and detection. Dopamine accomplishes these tasks through numerous, complex mechanisms in both neural structures. In this review, we provide an overview of the established and emerging research on these mechanisms and describe similarities and differences in dopamine expression and modulation of synaptic transmission in the retinas and OBs of various vertebrate organisms. This includes discussion of dopamine neurons’ morphologies, potential identities, and biophysical properties along with their contributions to circadian rhythms and stimulus-driven synthesis, activation, and release of dopamine. As dysregulation of some of these mechanisms may occur in patients with Parkinson’s disease, these symptoms are also discussed. The exploration and comparison of these two separate dopamine populations shows just how remarkably similar the retina and OB are, even though they are functionally distinct. It also shows that the modulatory properties of dopamine neurons are just as important to vision and olfaction as they are to motor coordination and neuropsychiatric/neurodegenerative conditions, thus, we hope this review encourages further research to elucidate these mechanisms.
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Affiliation(s)
- Kirill S Korshunov
- Department of Biological Science, Florida State University, Tallahassee, FL, United States.,Program in Neuroscience, Florida State University, Tallahassee, FL, United States
| | - Laura J Blakemore
- Department of Biological Science, Florida State University, Tallahassee, FL, United States.,Program in Neuroscience, Florida State University, Tallahassee, FL, United States
| | - Paul Q Trombley
- Department of Biological Science, Florida State University, Tallahassee, FL, United States.,Program in Neuroscience, Florida State University, Tallahassee, FL, United States
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21
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Bjørklund G, Dadar M, Anderson G, Chirumbolo S, Maes M. Preventive treatments to slow substantia nigra damage and Parkinson's disease progression: A critical perspective review. Pharmacol Res 2020; 161:105065. [PMID: 32652199 DOI: 10.1016/j.phrs.2020.105065] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 07/02/2020] [Accepted: 07/03/2020] [Indexed: 12/19/2022]
Abstract
Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway.
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | | | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; CONEM Scientific Secretary, Verona, Italy
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Impact Research Center, Deakin University, Geelong, Australia
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22
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Mendonça IP, Duarte-Silva E, Chaves-Filho AJM, Andrade da Costa BLDS, Peixoto CA. Neurobiological findings underlying depressive behavior in Parkinson's disease: A review. Int Immunopharmacol 2020; 83:106434. [PMID: 32224442 DOI: 10.1016/j.intimp.2020.106434] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 03/19/2020] [Indexed: 12/19/2022]
Abstract
Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases in the world with a harmful impact on the quality of life. Although its clinical diagnosis is based on motor symptoms such as resting tremor, postural instability, slow gait, and muscle stiffness, this disorder is also characterized by the presence of early emotional impairment, including features such as depression, anxiety, fatigue, and apathy. Depression is the main emotional manifestation associated with PD and the mechanisms involved in its pathophysiology have been extensively investigated however, it is not yet completely elucidated. In addition to monoaminergic imbalance, immunological and gut microbiota changes have been associated with depression in PD. Besides, a patient group appears be refractory to the treatment available currently. This review emphasizes the mainly neuromolecular findings of the PD-associated depression as well as discuss novel and potential pharmacological and non-pharmacological therapeutic strategies.
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Affiliation(s)
- Ingrid Prata Mendonça
- Laboratory of Ultrastructure, AggeuMagalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), PE, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco (UFPE), Brazil.
| | - Eduardo Duarte-Silva
- Laboratory of Ultrastructure, AggeuMagalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), PE, Brazil; Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/AggeuMagalhães Institute (IAM), Recife, PE, Brazil
| | - Adriano José Maia Chaves-Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - Christina Alves Peixoto
- Laboratory of Ultrastructure, AggeuMagalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ), PE, Brazil; National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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23
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Zahra W, Rai SN, Birla H, Singh SS, Rathore AS, Dilnashin H, Singh R, Keswani C, Singh RK, Singh SP. Neuroprotection of Rotenone-Induced Parkinsonism by Ursolic Acid in PD Mouse Model. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2020; 19:527-540. [PMID: 32787765 DOI: 10.2174/1871527319666200812224457] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/29/2020] [Accepted: 07/01/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Parkinson's Disease (PD) is characterized by both motor and non-motor symptoms. The presynaptic neuronal protein, α-Synuclein, plays a pivotal role in PD pathogenesis and is associated with both genetic and sporadic origin of the disease. Ursolic Acid (UA) is a well-known bioactive compound found in various medicinal plants, widely studied for its anti-inflammatory and antioxidant activities. OBJECTIVE In this research article, the neuroprotective potential of UA has been further explored in the Rotenone-induced mouse model of PD. METHODS To investigate our hypothesis, we have divided mice into 4 different groups, control, drug only control, Rotenone-intoxicated group, and Rotenone-intoxicated mice treated with UA. After the completion of dosing, behavioral parameters were estimated. Then mice from each group were sacrificed and the brains were isolated. Further, the biochemical tests were assayed to check the balance between the oxidative stress and endogenous anti-oxidants; and TH (Tyrosine Hydroxylase), α-Synuclein, Akt (Serine-threonine protein kinase), ERK (Extracellular signal-regulated kinase) and inflammatory parameters like Nuclear Factor-κB (NF-κB) and Tumor Necrosis Factor- α (TNF-α) were assessed using Immunohistochemistry (IHC). Western blotting was also done to check the expressions of TH and α-Synuclein. Moreover, the expression levels of PD related genes like α-Synuclein, β-Synuclein, Interleukin-1β (IL-1β), and Interleukin-10 (IL-10) were assessed by using Real-time PCR. RESULTS The results obtained in our study suggested that UA significantly reduced the overexpression of α-Synuclein and regulated the phosphorylation of survival-related kinases (Akt and ERK) apart from alleviating the behavioral abnormalities and protecting the dopaminergic neurons from oxidative stress and neuroinflammation. CONCLUSION Thus, our study shows the neuroprotective potential of UA, which can further be explored for possible clinical intervention.
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Affiliation(s)
- Walia Zahra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Sachchida Nand Rai
- Centre of Biotechnology, University of Allahabad, Prayagraj-211002, India
| | - Hareram Birla
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Saumitra Sen Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Aaina Singh Rathore
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Hagera Dilnashin
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Richa Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Chetan Keswani
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Rakesh K Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
| | - Surya Pratap Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India
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24
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Fedorova TN, Logvinenko AA, Poleshchuk VV, Muzychuk OA, Shabalina AA, Illarioshkin SN. Lipid Peroxidation Products in the Blood Plasma of Patients with Parkinson’s Disease as Possible Biomarkers of Different Stages of the Disease. NEUROCHEM J+ 2019. [DOI: 10.1134/s1819712419040020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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25
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Xie W, Meng X, Zhai Y, Ye T, Zhou P, Nan F, Sun G, Sun X. Antidepressant-like effects of the Guanxin Danshen formula via mediation of the CaMK II-CREB-BDNF signalling pathway in chronic unpredictable mild stress-induced depressive rats. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:564. [PMID: 31807545 DOI: 10.21037/atm.2019.09.39] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Depression is a chronic and recurrent syndrome of mood disorder causing immense social and economic burden; thus, treatment should be improved. Guanxin Danshen formula (GXDSF), a natural botanical drug composition prescription, has significant cardiovascular protective effects and is widely used in the clinical treatment of myocardial ischaemic diseases. However, it is still unclear and seldom studied whether GXDSF has neuroprotective effects against depressive disorders. This study explored whether GXDSF has antidepressant-like effects in rats exposed to chronic unpredictable mild stress (CUMS) and analysed the possible underlying neurotrophic expression and psychotropic mechanisms. Methods The present study was designed to investigate the antidepressant effects of GXDSF treatment in a CUMS-induced rat model. Based on the clinical doses, the drug-treated group was intragastrically administered GXDSF for 30 days, and rats were simultaneously exposed to CUMS stimulation for 30 days. After induction and drug administration, the depression-like behaviours were determined via the sucrose preference test (SPT), the open field test (OFT), the tail suspension test (TST), and the forced swim test (FST). ELISA kits were used to examine the monoaminergic neurotransmitters, monoamine oxidase (MAO) and Ca2+ levels in the hippocampus. Moreover, we measured and analysed the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels and the upstream regulation and signal pathways of BDNF and NGF to explore their related mechanisms in this animal model of depression, including calcium-calmodulin dependent protein kinase-II (CaMKII) and cAMP response element-binding (CREB). Results The results revealed that GXDSF may possess significant antidepressant-like effects via improving body weight, raising the sucrose preference in the SPT, increasing the total distance, the number of upright stands, and the residence time of the central zone in the open field test (OPF) and reducing the immobility time in the TST and FST. In addition, GXDSF significantly upregulated the relative levels of neurotransmitters, including dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in a dose-dependent manner and inhibited MAO activities in the hippocampus. Moreover, GXDSF reversed the decline in intracellular CREB and p-CREB expression induced by CUMS, downregulated the phosphorylation levels of intracellular CaMKII and its two subunits CaMKIIα and CaMKIIβ in the hippocampus, and thus, clearly upregulated the downstream effector protein expression levels of BDNF, NGF, and synitaxine-1 in the hippocampus. These data suggest that the antidepressant effects of GXDSF have a potential relationship with regulating changes in the CaMKII-CREB-BDNF pathway. Conclusions Despite several limitations of this study, the results have suggested that GXDSF administration possesses antidepressant-like effects in CUMS-treated rats and provide the first in vivo demonstration of a possible mechanism of GXDSF via regulating changes in the CaMKII-CREB-BDNF signalling pathway. These findings provide a novel potential substrate by which herbal antidepressants may exert therapeutic effects in the treatment of depression.
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Affiliation(s)
- Weijie Xie
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Xiangbao Meng
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Yadong Zhai
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Tianyuan Ye
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Ping Zhou
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Fengwei Nan
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Guibo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
| | - Xiaobo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China.,Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China
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26
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Mitochondrial Protection Promoted by the Coffee Diterpene Kahweol in Methylglyoxal-Treated Human Neuroblastoma SH-SY5Y Cells. Neurotox Res 2019; 37:100-110. [PMID: 31494842 DOI: 10.1007/s12640-019-00107-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/23/2019] [Accepted: 09/02/2019] [Indexed: 02/08/2023]
Abstract
The coffee diterpene kahweol (KW; C20H26O3) is a cytoprotective agent exhibiting potent antioxidant actions, as demonstrated in several experimental models. In spite of the efforts to elucidate exactly how KW promotes cytoprotection, it was not previously examined whether KW would be able to protect mitochondria of human cells undergoing redox stress. In the present work, we have treated the human neuroblastoma SH-SY5Y cell line with KW at 0.1-10 μM for 12 h prior to a challenge with methylglyoxal (MG), a reactive dicarbonyl that impairs mitochondrial function. We have found that KW at 10 μM suppressed the loss of mitochondrial membrane potential (MMP) and the bioenergetics decline (including decreased activity of the mitochondrial complexes I and V and reduced production of adenosine triphosphate, ATP) in the MG-treated SH-SY5Y cells. KW also prevented the MG-elicited generation of reactive oxygen and nitrogen species (ROS and RNS, respectively) in the SH-SY5Y cells. In this regard, KW exerted an antioxidant effect on the membranes of mitochondria obtained from the MG-treated cells. The mitochondria-related effects induced by KW were blocked by inhibition of the phosphoinositide 3-kinase (PI3K)/Akt or of the p38 mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, silencing of the transcription factor nuclear factor E2-related factor 2 (Nrf2) suppressed the mitochondrial protection promoted by KW in the MG-challenged cells. Therefore, KW protected mitochondria by a mechanism associated with the PI3K/Akt and p38 MAPK/Nrf2 signaling pathways.
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27
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Shaping the Nrf2-ARE-related pathways in Alzheimer's and Parkinson's diseases. Ageing Res Rev 2019; 54:100942. [PMID: 31415806 DOI: 10.1016/j.arr.2019.100942] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 08/02/2019] [Accepted: 08/09/2019] [Indexed: 12/20/2022]
Abstract
A failure in redox homeostasis is a common hallmark of Alzheimer's Disease (AD) and Parkinson's Disease (PD), two age-dependent neurodegenerative disorders (NDD), causing increased oxidative stress, oxidized/damaged biomolecules, altered neuronal function and consequent cell death. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-regulated transcription factor, results in upregulation of cytoprotective and antioxidant enzymes/proteins, protecting against oxidative stress. Nrf2 regulation is achieved by various proteins and pathways, at both cytoplasmatic and nuclear level; however, the elaborate network of mechanisms involved in Nrf2 regulation may restrain Nrf2 pathway normal activity. Indeed, altered Nrf2 activity is involved in aging and NDD, such as AD and PD. Therefore, understanding the diversity of Nrf2 control mechanisms and regulatory proteins is of high interest, since more effective NDD therapeutics can be identified. In this review, we first introduce Keap1-Nrf2-ARE structure, function and regulation, with a special focus on the several pathways involved in Nrf2 positive and negative modulation, namely p62, PKC, PI3K/Akt/GSK-3β, NF-kB and p38 MAPK. We then briefly describe the evidences for oxidative stress and Nrf2 pathway deregulation in different stages of NDDs. Finally, we discuss the potential of Nrf2-related pathways as potential therapeutic targets to possibly prevent or slowdown NDD progression.
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28
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Shan C, Gong YL, Zhuang QQ, Hou YF, Wang SM, Zhu Q, Huang GR, Tao B, Sun LH, Zhao HY, Li ST, Liu JM. Protective effects of β- nicotinamide adenine dinucleotide against motor deficits and dopaminergic neuronal damage in a mouse model of Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 2019; 94:109670. [PMID: 31220519 DOI: 10.1016/j.pnpbp.2019.109670] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 05/06/2019] [Accepted: 06/11/2019] [Indexed: 01/07/2023]
Abstract
The level of nicotinamide adenine dinucleotide (NAD) decreases in Parkinson's disease (PD), and its reduction has been reported to be involved in many age-associated neurodegenerative pathologies. Thus, we investigated whether NAD replenishment is beneficial in a 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. Preinjection with NAD in the striatum ameliorated motor deficits and dopaminergic neuronal damage in the substantia nigra and striatum of a mouse model of PD. Moreover, preincubation with NAD protected PC12 cells against the loss of cell viability, morphological damage, oxidative stress and mitochondrial dysfunction caused by 6-OHDA. These results add credence to the beneficial role of NAD against parkinsonian neurodegeneration in mouse models of PD, provide evidence for the potential of NAD for the prevention of PD, and suggest that NAD prevents pathological changes in PD via decreasing mitochondrial dysfunctions.
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Affiliation(s)
- Chang Shan
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Yan-Ling Gong
- Bio-X Institutes, Key laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qian-Qian Zhuang
- Bio-X Institutes, Key laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yan-Fang Hou
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Shu-Min Wang
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Qin Zhu
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Guo-Rui Huang
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Bei Tao
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Li-Hao Sun
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Hong-Yan Zhao
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China
| | - Sheng-Tian Li
- Bio-X Institutes, Key laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai 200025, China.
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29
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Hatziagapiou K, Kakouri E, Lambrou GI, Bethanis K, Tarantilis PA. Antioxidant Properties of Crocus Sativus L. and Its Constituents and Relevance to Neurodegenerative Diseases; Focus on Alzheimer's and Parkinson's Disease. Curr Neuropharmacol 2019; 17:377-402. [PMID: 29564976 PMCID: PMC6482475 DOI: 10.2174/1570159x16666180321095705] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 01/03/2018] [Accepted: 03/19/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Reactive oxygen species and reactive nitrogen species, which are collectively called reactive oxygen-nitrogen species, are the inevitable by-products of cellular metabolic redox reactions, such as oxidative phosphorylation in the mitochondrial respiratory chain, phagocytosis, reactions of biotransformation of exogenous and endogenous substrata in endoplasmic reticulum, eicosanoid synthesis, and redox reactions in the presence of metal with variable valence. Among medicinal plants, there is growing interest in Crocus Sativus L. It is a perennial, stemless herb, belonging to Iridaceae family, cultivated in various countries such as Greece, Italy, Spain, Israel, Morocco, Turkey, Iran, India, China, Egypt and Mexico. OBJECTIVE The present study aims to address the protective role of Crocus Sativus L. in neurodegeneration with an emphasis in Parkinson's and Alzheimer's disease. MATERIALS AND METHODS An electronic literature search was conducted by two of the authors from 1993 to August 2017. Original articles and systematic reviews (with or without meta-analysis), as well as case reports were selected. Titles and abstracts of papers were screened by a third reviewer to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. RESULTS Hence, the authors focused on the literature concerning the role of Crocus Sativus L. on its anti-oxidant and neuroprotective properties. CONCLUSION Literature findings represented in current review herald promising results for using Crocus Sativus L. and/or its active constituents as antioxidants, anti-inflammatory, and neuroprotective agents.
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Affiliation(s)
- Kyriaki Hatziagapiou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Hematology/Oncology Unit, Athens, Greece
| | - Eleni Kakouri
- Laboratory of Chemistry, Department of Food Science & Human Nutrition, School of Food Biotechnology and Development, Agricultural University of Athens, Athens, Greece
| | - George I Lambrou
- First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Hematology/Oncology Unit, Athens, Greece
| | - Kostas Bethanis
- Physics Laboratory, Department of Biotechnology, School of Food Biotechnology and Development, Agricultural University of Athens, Greece
| | - Petros A Tarantilis
- Laboratory of Chemistry, Department of Food Science & Human Nutrition, School of Food Biotechnology and Development, Agricultural University of Athens, Athens, Greece
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30
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Jiang N, Lv J, Wang H, Wang Q, Lu C, Yang Y, Huang H, Xia T, Lv G, Liu X. Antidepressant‐like effects of
20(
S
)‐protopanaxadiol
in a mouse model of chronic social defeat stress and the related mechanisms. Phytother Res 2019; 33:2726-2736. [DOI: 10.1002/ptr.6446] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/01/2019] [Accepted: 06/27/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Jing‐wei Lv
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Hai‐xia Wang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Qiong Wang
- Affiliated TCM Hospital/School of Pharmacy/Sino‐Portugal TCM International Cooperation CenterSouthwest Medical University Luzhou 646000 China
| | - Cong Lu
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yu‐jie Yang
- Affiliated TCM Hospital/School of Pharmacy/Sino‐Portugal TCM International Cooperation CenterSouthwest Medical University Luzhou 646000 China
| | - Hong Huang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Key Laboratory of Standardization of Chinese Herbal Medicine in Ministry of Education, School of PharmacyChengdu University of Traditional Chinese Medicine Chengdu 611137 China
| | - Tian‐ji Xia
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Guang‐hua Lv
- Key Laboratory of Standardization of Chinese Herbal Medicine in Ministry of Education, School of PharmacyChengdu University of Traditional Chinese Medicine Chengdu 611137 China
| | - Xin‐min Liu
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD)Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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Ahmadian E, Eftekhari A, Samiei M, Maleki Dizaj S, Vinken M. The role and therapeutic potential of connexins, pannexins and their channels in Parkinson's disease. Cell Signal 2019; 58:111-118. [DOI: 10.1016/j.cellsig.2019.03.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/10/2019] [Accepted: 03/10/2019] [Indexed: 02/07/2023]
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Kovel ES, Sachkova AS, Vnukova NG, Churilov GN, Knyazeva EM, Kudryasheva NS. Antioxidant Activity and Toxicity of Fullerenols via Bioluminescence Signaling: Role of Oxygen Substituents. Int J Mol Sci 2019; 20:ijms20092324. [PMID: 31083407 PMCID: PMC6539272 DOI: 10.3390/ijms20092324] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/04/2019] [Accepted: 05/09/2019] [Indexed: 12/17/2022] Open
Abstract
Fullerenols are nanosized water-soluble polyhydroxylated derivatives of fullerenes, a specific allotropic form of carbon, bioactive compounds, and perspective basis for drug development. Our paper analyzes the antioxidant activity and toxicity of a series of fullerenols with different number of oxygen substituents. Two groups of fullerenols were under investigation: (1) C60Oy(OH)x, C60,70Oy(OH)x, where x+y = 24–28 and (2) C60,70Oy(OH)x, Fe0,5C60Oy(OH)x, Gd@C82Oy(OH)x, where x+y = 40–42. Bioluminescent cellular and enzymatic assays (luminous marine bacteria and their enzymatic reactions, respectively) were applied to monitor toxicity in the model fullerenol solutions and bioluminescence was applied as a signaling physiological parameter. The inhibiting concentrations of the fullerenols were determined, revealing the fullerenols’ toxic effects. Antioxidant fullerenol’ ability was studied in solutions of model oxidizer, 1,4-benzoquinone, and detoxification coefficients of general and oxidative types (DGT and DOxT) were calculated. All fullerenols produced toxic effect at high concentrations (>0.01 g L−1), while their antioxidant activity was demonstrated at low and ultralow concentrations (<0.001 g L−1). Quantitative toxic and antioxidant characteristics of the fullerenols (effective concentrations, concentration ranges, DGT, and DOxT) were found to depend on the number of oxygen substituents. Lower toxicity and higher antioxidant activity were determined in solutions of fullerenols with fewer oxygen substituents (x+y = 24–28). The differences in fullerenol properties were attributed to their catalytic activity due to reversible electron acceptance, radical trapping, and balance of reactive oxygen species in aqueous solutions. The results provide pharmaceutical sciences with a basis for selection of carbon nanoparticles with appropriate toxic and antioxidant characteristics. Based on the results, we recommend, to reduce the toxicity of prospective endohedral gadolinium-fullerenol preparations Gd@C82Oy(OH)x, decreasing the number of oxygen groups to x+y = 24–28. The potential of bioluminescence methods to compare toxic and antioxidant characteristics of carbon nanostructures were demonstrated.
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Affiliation(s)
- Ekaterina S Kovel
- Institute of Biophysics SB RAS, FRC KSC SB RAS, 660036 Krasnoyarsk, Russia.
- Institute of Physics SB RAS, FRC KSC SB RAS, 660036 Krasnoyarsk, Russia.
| | - Anna S Sachkova
- National Research Tomsk Polytechnic University, 634050 Tomsk, Russia.
| | - Natalia G Vnukova
- Institute of Physics SB RAS, FRC KSC SB RAS, 660036 Krasnoyarsk, Russia.
- Siberian Federal University, 660041 Krasnoyarsk, Russia.
| | - Grigoriy N Churilov
- Institute of Physics SB RAS, FRC KSC SB RAS, 660036 Krasnoyarsk, Russia.
- Siberian Federal University, 660041 Krasnoyarsk, Russia.
| | - Elena M Knyazeva
- National Research Tomsk Polytechnic University, 634050 Tomsk, Russia.
| | - Nadezhda S Kudryasheva
- Institute of Biophysics SB RAS, FRC KSC SB RAS, 660036 Krasnoyarsk, Russia.
- Siberian Federal University, 660041 Krasnoyarsk, Russia.
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Wang XH, Zheng SS, Huang T, Su LM, Zhao YH, Souders CL, Martyniuk CJ. Fluazinam impairs oxidative phosphorylation and induces hyper/hypo-activity in a dose specific manner in zebrafish larvae. CHEMOSPHERE 2018; 210:633-644. [PMID: 30031347 DOI: 10.1016/j.chemosphere.2018.07.056] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 06/08/2023]
Abstract
Fluazinam is a pyridinamine fungicide that induces oxidative stress and mitochondrial damage in cells, and it has been reported to be neurotoxic. To characterize the biological effects of fluazinam, we assessed mitochondrial bioenergetics, dopamine system expression, and behavior of early life staged zebrafish (0.01 μM-0.5 μM). Fluazinam at environmentally-relevant levels did not induce sub-lethal effects in larvae, but at the LC50 (0.5 μM), fluazinam decreased basal and ATP-linked respiration significantly in embryos. As mitochondria are directly related to redox homeostasis and apoptosis, the expression of genes related to oxidative stress and apoptosis were measured. Superoxide dismutase 2 (sod2), heat stock protein 70 (hsp70), bcl2-associated X protein (bax), and caspase 9 (casp9) mRNA levels were up-regulated by 0.5 μM fluazinam. Taken together, there was evidence for mitochondrial dysfunction and oxidative damage at the highest concentration of fluazinam (0.5 μM) tested. As there are reports for fluazinam-induced neurotoxicity in dopamine synthesizing cells, transcriptional targets in the dopamine system were assessed in the zebrafish. Tyrosine hydroxylase 1 (th1) and dopamine receptor 2a (drd2a) mRNA levels were decreased by 0.5 μM fluazinam, suggesting that this fungicide may affect the dopaminergic system. To further assess the potential for fluazinam-mediated neuromodulation, the dark photokinesis response was assessed in larvae following exposure. Larvae exposed to 0.1 μM fluazinam showed hyperactivity, while larvae exposed to 0.2 and 0.3 μM showed hypo-activity. This study demonstrates that fluazinam disrupts mitochondrial bioenergetics in zebrafish, inducing an oxidative stress response, and aberrant behaviors in larvae that are dose dependent.
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Affiliation(s)
- Xiao H Wang
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, PR China; Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, UF Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, University of Florida, Gainesville, FL, 32611, USA
| | - Shan S Zheng
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, PR China
| | - Tao Huang
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, PR China
| | - Li M Su
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, PR China
| | - Yuan H Zhao
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, PR China.
| | - Christopher L Souders
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, UF Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, University of Florida, Gainesville, FL, 32611, USA
| | - Christopher J Martyniuk
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, UF Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, University of Florida, Gainesville, FL, 32611, USA.
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Singh SS, Rai SN, Birla H, Zahra W, Kumar G, Gedda MR, Tiwari N, Patnaik R, Singh RK, Singh SP. Effect of Chlorogenic Acid Supplementation in MPTP-Intoxicated Mouse. Front Pharmacol 2018; 9:757. [PMID: 30127737 PMCID: PMC6087758 DOI: 10.3389/fphar.2018.00757] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 06/21/2018] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress and neuroinflammation play a key role in dopaminergic (DA) neuronal degeneration, which results in the hindrance of normal ongoing biological processes in the case of Parkinson's disease. As shown in several studies, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, different behavioral parameters have suggested motor impairment and damage of antioxidant defence. Thus, some specific biological molecules found in medicinal plants can be used to inhibit the DA neuronal degeneration through their antioxidant and anti-inflammatory activities. With this objective, we studied chlorogenic acid (CGA), a naturally occurring polyphenolic compound, for its antioxidant and anti-inflammatory properties in MPTP-intoxicated mice. We observed significant reoccurrence of motor coordination and antioxidant defence on CGA supplementation, which has been in contrast with MPTP-injected mice. Moreover, in the case of CGA-treated mice, the enhanced expression of tyrosine hydroxylase (TH) within the nigrostriatal region has supported its beneficial effect. The activation of glial cells and oxidative stress levels were also estimated using inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP) immunoreactivity within substantia nigra (SN) and striatum of MPTP-injected mice. Administration of CGA has prevented the neuroinflammation in SN by regulating the nuclear factor-κB expression in the MPTP-induced group. The significant release of certain pro-inflammatory mediators such as tumor necrosis factor-α and interleukin (IL)-1β has also been inhibited by CGA with the enhanced expression of anti-inflammatory cytokine IL-10. Moreover, reduced GFAP staining within the nigrostriatal region has supported the fact that CGA has significantly helped in the attenuation of astrocyte activation. Hence, our study has shown that CGA supplementation shows its therapeutic ability by reducing the oxidative stress and neuroinflammation in MPTP-intoxicated mice.
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Affiliation(s)
- Saumitra S. Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sachchida N. Rai
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Hareram Birla
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Walia Zahra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Gaurav Kumar
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Mallikarjuna R. Gedda
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Neeraj Tiwari
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ranjana Patnaik
- School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Rakesh K. Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Surya P. Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
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Tana C, Ticinesi A, Prati B, Nouvenne A, Meschi T. Uric Acid and Cognitive Function in Older Individuals. Nutrients 2018; 10:nu10080975. [PMID: 30060474 PMCID: PMC6115794 DOI: 10.3390/nu10080975] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/23/2018] [Accepted: 07/26/2018] [Indexed: 01/08/2023] Open
Abstract
Hyperuricemia has been recognized as an independent cardiovascular risk factor in epidemiological studies. However, uric acid can also exert beneficial functions due to its antioxidant properties, which may be particularly relevant in the context of neurodegenerative diseases. In this paper, we critically revise the evidence on the relationship between serum uric acid levels and cognitive function in older individuals, focusing on the etiology of cognitive impairment (Alzheimer’s disease, Parkinson’s dementia, and vascular dementia) and on the interactive connections between uric acid, dementia, and diet. Despite high heterogeneity in the existing studies, due to different characteristics of studied populations and methods of cognitive dysfunction assessment, we conclude that serum uric acid may modulate cognitive function in a different way according to the etiology of dementia. Current studies indeed demonstrate that uric acid may exert neuroprotective actions in Alzheimer’s disease and Parkinson’s dementia, with hypouricemia representing a risk factor for a quicker disease progression and a possible marker of malnutrition. Conversely, high serum uric acid may negatively influence the disease course in vascular dementia. Further studies are needed to clarify the physio-pathological role of uric acid in different dementia types, and its clinical-prognostic significance.
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Affiliation(s)
- Claudio Tana
- Internal Medicine and Critical Subacute Care Unit, Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43125 Parma, Italy.
| | - Andrea Ticinesi
- Internal Medicine and Critical Subacute Care Unit, Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43125 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Beatrice Prati
- Internal Medicine and Critical Subacute Care Unit, Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43125 Parma, Italy.
| | - Antonio Nouvenne
- Internal Medicine and Critical Subacute Care Unit, Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43125 Parma, Italy.
| | - Tiziana Meschi
- Internal Medicine and Critical Subacute Care Unit, Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43125 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
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Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology. Molecules 2018; 23:molecules23040940. [PMID: 29673237 PMCID: PMC6017639 DOI: 10.3390/molecules23040940] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/04/2018] [Accepted: 04/06/2018] [Indexed: 12/28/2022] Open
Abstract
Panax notoginseng (Burk) F. H. Chen, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis, and neuronal protection, and its main ingredients are Panax notoginseng saponins (PNS). Currently, Panax notoginseng (Burk) F. H. Chen may improve mental function, have anti-insomnia and anti-depression effects, alleviate anxiety, and decrease neural network excitation. However, the underlying effects and the mechanisms of Panax notoginseng (Burk) F. H. Chen and its containing chemical constituents (PNS) on these depression-related or anxiety-related diseases has not been completely established. This review summarized the antidepressant or anxiolytic effects and mechanisms of PNS and analyzed network targets of antidepressant or anxiolytic actions with network pharmacology tools to provide directions and references for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development. The review showed PNS and its components may exert these effects through regulating neurotransmitter mechanism (5-HT, DA, NE), modulation of the gamma-amino butyric acid (GABA) neurotransmission, glutamatergic system, hypo-thalamus-pituitary-adrenal (HPA) axis, brain-derived neurotrophic factor (BDNF), and its intracellular signaling pathways in the central nervous system; and produce neuronal protection by anti-inflammatory, anti-oxidation, or inhibition of neuronal apoptosis, or platelet aggregation and its intracellular signaling pathways. Network target analysis indicated PNS and its components also may have anti-inflammatory and anti-apoptotic effects, which leads to the preservation of brain nerves, and regulate the activity and secretion of nerve cells, exerting anti-depression and anxiolytic effects, which may provide new directions for further in-depth researches of related mechanisms.
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Morshedi M, Valenlia KB, Hosseinifard ES, Shahabi P, Abbasi MM, Ghorbani M, Barzegari A, Sadigh-Eteghad S, Saghafi-Asl M. Beneficial psychological effects of novel psychobiotics in diabetic rats: the interaction among the gut, blood and amygdala. J Nutr Biochem 2018; 57:145-152. [PMID: 29730508 DOI: 10.1016/j.jnutbio.2018.03.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/20/2018] [Accepted: 03/21/2018] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) can lead to major complications such as psychiatric disorders which include depressive and anxiety-like behaviors. The association of the gut-brain axis in the development of such disorders, especially in T2DM, has been elucidated; however, gut dysbiosis is also reported in patients with T2DM. Hence, the regulation of the gut-brain axis, in particular, the gut-amygdala, as a vital region for the regulation of behavior is essential. Thirty-five male Wistar rats were divided into six groups. To induce T2DM, treatment groups received high-fat diet and 35 mg/kg streptozotocin. Then, supplements of Lactobacillus plantarum, inulin or their combination were administered to each group for 8 weeks. Finally, the rats were sacrificed for measurement of blood and tissue parameters after behavioral testing. The findings demonstrated the favorable effects of the psychobiotics (L. plantarum, inulin or their combination) on oxidative markers of the blood and amygdala (superoxide dismutase, glutathione peroxidase, malondialdehyde and total antioxidant capacity), as well as on concentrations of amygdala serotonin and brain-derived neurotrophic factor, in the diabetic rats. In addition, beneficial effects were observed on the elevated plus maze and forced swimming tests with no change in locomotor activity of the rats. There was a strong correlation between the blood and amygdala oxidative markers, insulin and fasting blood sugar with depressive and anxiety-like behaviors. Our results identified L. plantarum ATCC 8014 and inulin or their combination as novel psychobiotics that could improve the systemic and nervous antioxidant status and improve amygdala performance and beneficial psychotropic effects.
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Affiliation(s)
- Mohammad Morshedi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khadijeh Bavafa Valenlia
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elaheh Sadat Hosseinifard
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parviz Shahabi
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz, Iran
| | | | - Meysam Ghorbani
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Barzegari
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Saghafi-Asl
- Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz, Iran; Department of Biochemistry and Diet Therapy, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Frandsen JR, Narayanasamy P. Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway. Redox Biol 2018; 14:465-473. [PMID: 29080525 PMCID: PMC5680520 DOI: 10.1016/j.redox.2017.10.015] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/11/2017] [Accepted: 10/17/2017] [Indexed: 12/21/2022] Open
Abstract
The glyoxalase pathway functions to detoxify reactive dicarbonyl compounds, most importantly methylglyoxal. The glyoxalase pathway is an antioxidant defense mechanism that is essential for neuroprotection. Excessive concentrations of methylglyoxal have deleterious effects on cells, leading to increased levels of inflammation and oxidative stress. Neurodegenerative diseases - including Alzheimer's, Parkinson's, Aging and Autism Spectrum Disorder - are often induced or exacerbated by accumulation of methylglyoxal. Antioxidant compounds possess several distinct mechanisms that enhance the glyoxalase pathway and function as neuroprotectants. Flavonoids are well-researched secondary plant metabolites that appear to be effective in reducing levels of oxidative stress and inflammation in neural cells. Novel flavonoids could be designed, synthesized and tested to protect against neurodegenerative diseases through regulating the glyoxalase pathway.
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Affiliation(s)
- Joel R Frandsen
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA
| | - Prabagaran Narayanasamy
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA.
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Polyakova VO, Kvetnoy IM, Anderson G, Rosati J, Mazzoccoli G, Linkova NS. Reciprocal Interactions of Mitochondria and the Neuroimmunoendocrine System in Neurodegenerative Disorders: An Important Role for Melatonin Regulation. Front Physiol 2018; 9:199. [PMID: 29593561 PMCID: PMC5857592 DOI: 10.3389/fphys.2018.00199] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 02/23/2018] [Indexed: 12/14/2022] Open
Abstract
Structural and functional alterations of mitochondria are intimately linked to a wide array of medical conditions. Many factors are involved in the regulation of mitochondrial function, including cytokines, chaperones, chemokines, neurosteroids, and ubiquitins. The role of diffusely located cells of the neuroendocrine system, including biogenic amines and peptide hormones, in the management of mitochondrial function, as well as the role of altered mitochondrial function in the regulation of these cells and system, is an area of intense investigation. The current article looks at the interactions among the cells of the neuronal-glia, immune and endocrine systems, namely the diffuse neuroimmunoendocrine system (DNIES), and how DNIES interacts with mitochondrial function. Whilst changes in DNIES can impact on mitochondrial function, local, and systemic alterations in mitochondrial function can alter the component systems of DNIES and their interactions. This has etiological, course, and treatment implications for a wide range of medical conditions, including neurodegenerative disorders. Available data on the role of melatonin in these interactions, at cellular and system levels, are reviewed, with directions for future research indicated.
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Affiliation(s)
- Victoria O Polyakova
- Department of Gynecology and Reproductology, Ott Institute of Obstetrics, Saint Petersburg, Russia.,Department of Cell Biology and Pathology, Saint-Petersburg Institute of Bioregulation and Gerontology, Saint Petersburg, Russia.,Department of Physiology and Department of Pathology, Saint Petersburg State University, Saint Petersburg, Russia
| | - Igor M Kvetnoy
- Department of Gynecology and Reproductology, Ott Institute of Obstetrics, Saint Petersburg, Russia.,Department of Cell Biology and Pathology, Saint-Petersburg Institute of Bioregulation and Gerontology, Saint Petersburg, Russia.,Department of Physiology and Department of Pathology, Saint Petersburg State University, Saint Petersburg, Russia
| | - George Anderson
- CRC Scotland and London Clinical Research, London, United Kingdom
| | - Jessica Rosati
- Cell Reprogramming Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Natalya S Linkova
- Department of Cell Biology and Pathology, Saint-Petersburg Institute of Bioregulation and Gerontology, Saint Petersburg, Russia.,Peter the Great Saint Petersburg Polytechnic University, Saint Petersburg, Russia
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40
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Anderson G. Linking the biological underpinnings of depression: Role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:255-266. [PMID: 28433458 DOI: 10.1016/j.pnpbp.2017.04.022] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/01/2017] [Indexed: 01/08/2023]
Abstract
The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and melatonergic pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective phenomenology.
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Keck F, Kortchak S, Bakovic A, Roberts B, Agrawal N, Narayanan A. Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells. Virulence 2018; 9:1403-1421. [PMID: 30101649 PMCID: PMC6141141 DOI: 10.1080/21505594.2018.1509668] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 07/31/2018] [Indexed: 12/16/2022] Open
Abstract
Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11-7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.
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Affiliation(s)
- Forrest Keck
- National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA
| | - Stephanie Kortchak
- National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA
| | - Allison Bakovic
- National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA
| | | | - Nitin Agrawal
- Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, USA
| | - Aarthi Narayanan
- National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, USA
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Lu JYD, Su P, Barber JEM, Nash JE, Le AD, Liu F, Wong AHC. The neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage. PeerJ 2017; 5:e3933. [PMID: 29062606 PMCID: PMC5651169 DOI: 10.7717/peerj.3933] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 09/26/2017] [Indexed: 12/20/2022] Open
Abstract
Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.
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Affiliation(s)
- Justin Y D Lu
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - Ping Su
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - James E M Barber
- Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto, Scarborough, Toronto, Ontario, Canada
| | - Joanne E Nash
- Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto, Scarborough, Toronto, Ontario, Canada
| | - Anh D Le
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Fang Liu
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Albert H C Wong
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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43
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Ziomkiewicz A, Frumkin A, Zhang Y, Sancilio A, Bribiescas RG. The cost of reproduction in women: Reproductive effort and oxidative stress in premenopausal and postmenopausal American women. Am J Hum Biol 2017; 30. [PMID: 28984395 DOI: 10.1002/ajhb.23069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 09/06/2017] [Accepted: 09/19/2017] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Life history theory predicts a trade-off between female investment in reproduction and somatic maintenance, which can result in accelerated senescence. Oxidative stress has been shown to be a causal physiological mechanism for accelerated aging and a possible contributor to this trade-off. We aimed to test the hypothesis for the existence of significant associations between measures of reproductive effort and the level of oxidative stress biomarkers in premenopausal and postmenopausal American women. METHODS Serum samples and questionnaire data were collected from 63 premenopausal and postmenopausal women (mean age 53.4 years), controls in the Connecticut Thyroid Health Study, between May 2010 and December 2013. Samples were analyzed for levels of 8-OHdG and Cu/Zn-SOD using immunoassay method. RESULTS Levels of oxidative damage (8-OHdG) but not oxidative defense (Cu/Zn-SOD) were negatively associated with parity and number of sons in premenopausal women (r = -0.52 for parity, r = -0.52 for number of sons, P < .01). Together, measures of reproductive effort, women's BMI, age, and menopausal status explained around 15% of variance in level of 8-OHdG. No association between reproductive effort characteristics and oxidative damage was found for postmenopausal women. CONCLUSIONS We found no evidence of a trade-off between somatic maintenance as measured by 8-OHdG and reproductive effort in women from this American population. On the contrary, higher gravidity and parity in premenopausal women was associated with lower damage to cellular DNA caused by oxidative stress. These results highlight the importance of population variation and environmental conditions when testing the occurrence of life-history trade-offs.
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Affiliation(s)
- Anna Ziomkiewicz
- Polish Academy of Sciences, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, 50-449, Poland.,Department of Anthropology, Yale University, New Haven, Connecticut 06511
| | - Amara Frumkin
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut 06511
| | - Yawei Zhang
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut 06510.,Yale School of Public Health, Department of Environmental Health Sciences, New Haven, Connecticut 06510
| | - Amelia Sancilio
- Department of Anthropology, Yale University, New Haven, Connecticut 06511
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Kanchanatawan B, Sirivichayakul S, Thika S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Noto C, Ivanova R, Maes M. Physio-somatic symptoms in schizophrenia: association with depression, anxiety, neurocognitive deficits and the tryptophan catabolite pathway. Metab Brain Dis 2017; 32:1003-1016. [PMID: 28258445 DOI: 10.1007/s11011-017-9982-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/23/2017] [Indexed: 12/12/2022]
Abstract
To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their relation to positive, negative and affective symptoms; neurocognitive deficits and impairments in the tryptophan catabolite (TRYCAT) pathway. Eighty four patients with schizophrenia and 40 healthy controls were assessed using the 12 item Fibromyalgia and Chronic Fatigue Syndrome Rating scale (FF) and scales for negative and positive symptoms, depression and anxiety. Cognitive functioning was tested using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Other assessments included: immunoglobulin (Ig)A and IgM responses to tryptophan catabolites (TRYCATs), namely quinolinic (QA), 3-OH-kynurenine (3HK), picolinic (PA), xanthurenic (XA) and kynurenic acid (KA) and anthranilic acid (AA). More than 50% of the patients studied had elevated levels of physio-somatic (PS) symptoms, significantly co-occurring with depression and anxiety, but not with negative or positive symptoms. PS symptoms were significantly associated with IgA/IgM responses to TRYCATs, including increased IgA responses to 3 HK, PA and XA, and lowered IgA to QA and AA. Fatigue, muscle pain and tension, autonomic and cognitive symptoms and a flu-like malaise were strongly associated with cognitive impairments in spatial planning and working memory, paired associative learning, visual sustained attention and attention set shifting. PS symptoms in schizophrenia aggregate with depression and anxiety symptoms and may be driven by TRYCAT patterning of IgA/IgM-responses, with IgA indicating mucosal-mediated changes and IgM indicating regulatory functions. As such, the patterning of IgA/IgM responses to TRYCATs may indicate differential TRYCATs regulation of neuronal and glia activity that act to regulate PS signalling in schizophrenia.
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Affiliation(s)
- Buranee Kanchanatawan
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Supaksorn Thika
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kiat Ruxrungtham
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - André F Carvalho
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Michel Geffard
- Research Department, IDRPHT, Talence, France
- GEMAC, Saint Jean d'Illac, France
| | | | - Cristiano Noto
- Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil
| | - Rada Ivanova
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
- Department of Psychiatry, Faculty of Medicine, State University of Londrina, Londrina, Brazil.
- Revitalis, Waalre, the Netherlands.
- IMPACT Strategic Research Center, Deakin University, Geelong, Australia.
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45
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Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Prog Neurobiol 2017; 155:76-95. [DOI: 10.1016/j.pneurobio.2015.12.009] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 12/18/2015] [Accepted: 12/30/2015] [Indexed: 12/14/2022]
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Go YM, Jones DP. Redox theory of aging: implications for health and disease. Clin Sci (Lond) 2017; 131:1669-1688. [PMID: 28667066 PMCID: PMC5773128 DOI: 10.1042/cs20160897] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/15/2017] [Accepted: 05/18/2017] [Indexed: 02/07/2023]
Abstract
Genetics ultimately defines an individual, yet the phenotype of an adult is extensively determined by the sequence of lifelong exposures, termed the exposome. The redox theory of aging recognizes that animals evolved within an oxygen-rich environment, which created a critical redox interface between an organism and its environment. Advances in redox biology show that redox elements are present throughout metabolic and structural systems and operate as functional networks to support the genome in adaptation to environmental resources and challenges during lifespan. These principles emphasize that physical and functional phenotypes of an adult are determined by gene-environment interactions from early life onward. The principles highlight the critical nature of cumulative exposure memories in defining changes in resilience progressively during life. Both plasma glutathione and cysteine systems become oxidized with aging, and the recent finding that cystine to glutathione ratio in human plasma predicts death in coronary artery disease (CAD) patients suggests this could provide a way to measure resilience of redox networks in aging and disease. The emerging concepts of cumulative gene-environment interactions warrant focused efforts to elucidate central mechanisms by which exposure memory governs health and etiology, onset and progression of disease.
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Affiliation(s)
- Young-Mi Go
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, U.S.A
| | - Dean P Jones
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, U.S.A.
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Korshunov KS, Blakemore LJ, Trombley PQ. Dopamine: A Modulator of Circadian Rhythms in the Central Nervous System. Front Cell Neurosci 2017; 11:91. [PMID: 28420965 PMCID: PMC5376559 DOI: 10.3389/fncel.2017.00091] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 03/15/2017] [Indexed: 01/11/2023] Open
Abstract
Circadian rhythms are daily rhythms that regulate many biological processes – from gene transcription to behavior – and a disruption of these rhythms can lead to a myriad of health risks. Circadian rhythms are entrained by light, and their 24-h oscillation is maintained by a core molecular feedback loop composed of canonical circadian (“clock”) genes and proteins. Different modulators help to maintain the proper rhythmicity of these genes and proteins, and one emerging modulator is dopamine. Dopamine has been shown to have circadian-like activities in the retina, olfactory bulb, striatum, midbrain, and hypothalamus, where it regulates, and is regulated by, clock genes in some of these areas. Thus, it is likely that dopamine is essential to mechanisms that maintain proper rhythmicity of these five brain areas. This review discusses studies that showcase different dopaminergic mechanisms that may be involved with the regulation of these brain areas’ circadian rhythms. Mechanisms include how dopamine and dopamine receptor activity directly and indirectly influence clock genes and proteins, how dopamine’s interactions with gap junctions influence daily neuronal excitability, and how dopamine’s release and effects are gated by low- and high-pass filters. Because the dopamine neurons described in this review also release the inhibitory neurotransmitter GABA which influences clock protein expression in the retina, we discuss articles that explore how GABA may contribute to the actions of dopamine neurons on circadian rhythms. Finally, to understand how the loss of function of dopamine neurons could influence circadian rhythms, we review studies linking the neurodegenerative disease Parkinson’s Disease to disruptions of circadian rhythms in these five brain areas. The purpose of this review is to summarize growing evidence that dopamine is involved in regulating circadian rhythms, either directly or indirectly, in the brain areas discussed here. An appreciation of the growing evidence of dopamine’s influence on circadian rhythms may lead to new treatments including pharmacological agents directed at alleviating the various symptoms of circadian rhythm disruption.
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Affiliation(s)
- Kirill S Korshunov
- Program in Neuroscience, Florida State University,Tallahassee, FL, USA.,Department of Biological Science, Florida State University,Tallahassee, FL, USA
| | - Laura J Blakemore
- Program in Neuroscience, Florida State University,Tallahassee, FL, USA.,Department of Biological Science, Florida State University,Tallahassee, FL, USA
| | - Paul Q Trombley
- Program in Neuroscience, Florida State University,Tallahassee, FL, USA.,Department of Biological Science, Florida State University,Tallahassee, FL, USA
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de Oliveira MR, da Costa Ferreira G, Peres A, Bosco SMD. Carnosic Acid Suppresses the H 2O 2-Induced Mitochondria-Related Bioenergetics Disturbances and Redox Impairment in SH-SY5Y Cells: Role for Nrf2. Mol Neurobiol 2017; 55:968-979. [PMID: 28084591 DOI: 10.1007/s12035-016-0372-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 12/28/2016] [Indexed: 12/20/2022]
Abstract
The phenolic diterpene carnosic acid (CA, C20H28O4) exerts antioxidant, anti-inflammatory, anti-apoptotic, and anti-cancer effects in mammalian cells. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2), among other signaling pathways, and restores cell viability in several in vitro and in vivo experimental models. We have previously reported that CA affords mitochondrial protection against various chemical challenges. However, it was not clear yet whether CA would prevent chemically induced impairment of the tricarboxylic acid cycle (TCA) function in mammalian cells. In the present work, we found that a pretreatment of human neuroblastoma SH-SY5Y cells with CA at 1 μM for 12 h prevented the hydrogen peroxide (H2O2)-induced impairment of the TCA enzymes (aconitase, α-ketoglutarate dehydrogenase (α-KGDH), succinate dehydrogenase (SDH)) and abolished the inhibition of the complexes I and V and restored the levels of ATP by a mechanism associated with Nrf2. CA also exhibited antioxidant abilities by enhancing the levels of reduced glutathione (GSH) and decreasing the content oxidative stress markers (cellular 8-oxo-2'-deoxyguanosine (8-oxo-dG), and mitochondrial malondialdehyde (MDA), protein carbonyl, and 3-nitrotyrosine). Silencing of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects elicited by CA in mitochondria of SH-SY5Y cells. Therefore, CA prevented the H2O2-triggered mitochondrial impairment by an Nrf2-dependent mechanism. The specific role of Nrf2 in ameliorating the function of TCA enzymes function needs further research.
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Affiliation(s)
- Marcos Roberto de Oliveira
- Departamento de Química/ICET, Universidade Federal de Mato Grosso (UFMT), Av. Fernando Corrêa da Costa , 2367 , Cuiaba, MT, 78060-900, Brazil.
| | - Gustavo da Costa Ferreira
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Alessandra Peres
- Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
- Centro de Pesquisa da Pós-Graduação, Centro Universitário Metodista IPA, Porto Alegre, RS, Brazil
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de Oliveira MR, de Souza ICC, Fürstenau CR. Carnosic Acid Induces Anti-Inflammatory Effects in Paraquat-Treated SH-SY5Y Cells Through a Mechanism Involving a Crosstalk Between the Nrf2/HO-1 Axis and NF-κB. Mol Neurobiol 2017; 55:890-897. [DOI: 10.1007/s12035-017-0389-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 01/04/2017] [Indexed: 12/13/2022]
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50
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de Oliveira MR, Peres A, Ferreira GC, Schuck PF, Gama CS, Bosco SMD. Carnosic Acid Protects Mitochondria of Human Neuroblastoma SH-SY5Y Cells Exposed to Paraquat Through Activation of the Nrf2/HO-1Axis. Mol Neurobiol 2016; 54:5961-5972. [DOI: 10.1007/s12035-016-0100-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 09/05/2016] [Indexed: 12/21/2022]
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